Faculty

Christopher M. Adams M.D., Ph.D.
Professor
Internal Medicine

Our laboratory studies the genetic control of mammalian metabolism. Currently, we are focusing on an evolutionarily ancient transcription factor called ATF4, which activates over twenty genes that cells use to take up and synthesize amino acids. Our projects include biochemical studies of cultured cells to determine how ATF4 is regulated by hormones and nutrients, and how ATF4 and downstream genes influence anabolic growth in cells; studies in transgenic and knockout mice to explore the role of ATF4 in skeletal muscle, the major tissue repository of amino acids and protein; and translational studies of skeletal muscle gene expression in human patients with muscle atrophy, a common and debilitating complication of many different illnesses ranging from diabetes to cancer.

Research Modes

Experimental

Research Paradigms

Mutation, Sequencing and Variant Detection, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Endocrine System, Metabolism and Nutrition

Organisms

Human, Rodent (mouse/rat)
Ferhaan  Ahmad M.D., Ph.D.
Associate Professor of Internal Medicine and Radiology
Department of Internal Medicine, Division of Cardiovascular Medicine

Dr. Ahmad is the Director of the Cardiovascular Genetics Program at the University of Iowa, which brings together basic scientists at the Carver College of Medicine and clinicians at the University of Iowa Hospitals and Clinics (UIHC) who are focusing on heritable cardiovascular disorders. He directs a laboratory conducting basic and translational research into the genetic and genomic mechanisms underlying inherited cardiovascular disorders, including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, glycogen storage cardiomyopathy, inherited arrhythmias, and pulmonary hypertension. His laboratory uses laboratory uses a wide range of techniques in human and mouse genetics and genomics, and fosters crosstalk between clinical studies, human molecular genetic studies, animal modeling, basic cellular and molecular studies, and computational systems biology analyses. At the UIHC Cardiovascular Genetics Clinic, an interdisciplinary team evaluates, counsels, and treats patients with inherited cardiovascular disorders and their families.

Research Modes

Clinical, Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, DNA Methylation and Epigenetics, Genetic Association Studies, Genetic Engineering, MiRNA and Post-transcriptional Regulation, Mutation, Network and Systems Biology, Non-coding RNA, Population Genetics, Sequencing and Variant Detection, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Cardiovascular System, Endocrine System, Metabolism and Nutrition, Respiratory System

Organisms

Human, Rodent (mouse/rat), Swine
Michael G Anderson Ph.D.
Associate Professor
Molecular Physiology & Biophysics

Research in my laboratory is aimed at understanding fundamental physiological properties of the eye and the pathophysiological mechanisms underlying a variety of complex eye diseases. Of primary interest are the glaucomas, a leading cause of blindness that affects approximately 70 million people worldwide. Glaucoma typically involves three types of events: molecular insults compromising the anterior chamber, increased intraocular pressure, and neurodegenerative retinal ganglion cell loss. Not surprisingly, the biological relationships linking these events are complex. Our approach for studying these events is founded in functional mouse genetics and supplemented by a variety of molecular, cellular, immunological, and neurobiological techniques. The premise for this approach is that stringently performed genetic studies offer great potential for overcoming the natural biological complexity of glaucoma. Current projects in the lab involve mouse models of pigmentary glaucoma and are testing the hypotheses that aberrant melanosomal processes and inflammation are potent contributors to this form of glaucoma. We are also interested in new mouse models of glaucoma and are developing mouse ES cell based genetic strategies for fostering the discovery of new glaucomatous mechanisms. In the long term, these studies will contribute to an increased understanding of eye diseases such as glaucoma, and ultimately to improved human therapies.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Genetic Association Studies, Genetic Engineering, Imaging, MiRNA and Post-transcriptional Regulation, Mutation, Network and Systems Biology, Non-coding RNA, Sequencing and Variant Detection

Applications

Ageing, Development and Dysmorphology, Eye and Vision

Organisms

Rodent (mouse/rat)
Kin Fai  Au Ph.D.
Assistant Professor
Internal Medicine, Pulmonary

We are interested in methodology research of Third Generation Sequencing (TGS) (especially for PacBio and Oxford Nanopore sequencing). Au lab is working on both hybrid sequencing (Second Generation Sequencing (SGS) + TGS) and TGS-alone methodology research. Our research interests include but not limited to alternative splicing, isoform construction, gene fusion and quantitative analysis.

Stem cell transcriptome analysis

Au lab is applying the hybrid sequencing method on ESC, iPSC and preimplantation embryo, to deeply study the transcriptome differences between stem cells.

Proteomics

Protein identification and novel splice detections from tandem Mass Spec are our research interests. Au lab is developing statistical methods for Integration of Mass Spec and sequencing data, in order to solve difficult proteomics problems.

In addition, we are interested in the methodology research of gene regulatory network and RNA editing.

Research Modes

Computational

Research Paradigms

MiRNA and Post-transcriptional Regulation, Sequencing and Variant Detection, Splicing, Transcription and Transcriptional Regulation

Applications

Cancer, Stem Cells

Organisms

Human, Rodent (mouse/rat)
Alex G Bassuk M.D., Ph.D.
Associate Professor
Pediatrics

Our laboratory is interested in understanding the basic mechanisms underlying both normal and disordered development of the nervous system. Our approach to these issues includes investigating the genetics of human neural tube defects (NTDs) and familial epilepsies, and elucidating the biology regulating neural stem cell development. The techniques used in our laboratory include genome wide linkage analysis (GWA), association studies, comparative genomic hybridization (CGH), copy number variation (CNV) analysis, transgenic mouse production, and cell culture. As part of our studies we have collected DNA samples from over 2000 patients and family members with congenital nervous system malformations, and several large families with autosomal recessive epilepsy syndromes.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Association Studies, Mutation, Sequencing and Variant Detection

Applications

Development and Dysmorphology, Nervous System

Organisms

Human, Rodent (mouse/rat)
Terry Braun
Associate Professor
Biomedical Engineering, Ophthalmology

I have been involved in the application of high-performance computing technologies to the challenges of disease gene identification and mutation screening. My efforts, in collaboration with members of the College of Medicine, have involved the design of novel techniques utilizing networked systems to analyze genomic sequence and annotation. This also includes the integration of detailed phenotypic data (clinical data) with molecular data (the results of wet-lab experiments). The techniques need to be adaptable so that they may utilize recent and future high-throughput technologies (microarrays, protoeomics, SNPs, etc.). The tools derived from these techniques are actively being applied to identify disease-causing mutations for glaucoma, macular degeneration, autism, retinitis pigmentosa, Bardet-Biedle syndrome, and others, and may lead to better understanding of the pathophysiology of these disorders.

Research Modes

Computational

Research Paradigms

Cellular Signalling Pathways, DNA Methylation and Epigenetics, Genetic Association Studies, Genetic Engineering, Machine Learning, Mutation, Network and Systems Biology, Protein Folding and Structure, Protein-protein Interactions, Sequencing and Variant Detection

Applications

Cancer, Eye and Vision, Hearing

Organisms

Human
Charles Brenner Ph.D.
Professor and Head
Biochemistry & Internal Medicine

Cellular function and differentiation depend on an ability to read environmental cues and to execute a gene expression program that is appropriate to time, place and context.  Nutrient availability is among the most important signals to which cells respond.  Importantly, nutrients are not only transmitted from outside an organism, i.e., by feeding, but are also transmitted from cell to cell and from tissue to tissue.  Metabolic control of gene expression is critical to the maintenance of cellular longevity.  Dysregulation of the nutritional control of gene expression underlies a series of conditions including nondetection of satiety, which can lead to obesity and diabetes, and diseases such as cancer.

Our laboratory is engaged in several projects that dissect specific problems in the metabolic control of gene expression.  In particular, we are interested in how changing environmental conditions lead to reversible transfer of two carbon, i.e. acetyl, and one carbon, i.e. methyl, groups to proteins and DNA, respectively.  These processes are fundamentally important because two carbon transfers link carbohydrate and fat metabolism to nicotinamide adenine dinucleotide (NAD) biosynthesis and because one carbon transfers link the folate cycle and methionine biosynthesis to S-adenosyl methionine metabolism. Trainees in our group are engaged in interdisciplinary projects, performing protein purification, enzymology, structural biology, yeast and somatic cell genetics, genomics, and chemical biology.

Research Modes

Clinical, Experimental

Research Paradigms

Cellular Signalling Pathways, DNA Methylation and Epigenetics, Gene-environment Interactions and Interplay, Network and Systems Biology, Translation and Post-translational Modifications

Applications

Ageing, Cancer, Metabolism and Nutrition

Organisms

Human, Rodent (mouse/rat), Yeast and Fungi
Thomas L Casavant Ph.D.
Professor
Biomedical, Electrical and Computer Engineering; Ophthalmology

My research is divided among two areas: 1. High-Performance Parallel and Distributed Computing; and 2. Gene Discovery, Mapping, and Disease Linkage. Since 1986, my work in High-Performance Parallel and Distributed Computing has involved the theory, design, and prototyping of computer systems to solve the largest and most computationally demanding problems. This work involves the design of hardware, software, and the networking/communications to interconnect them. The two patents I hold are for the design of a parallel computing systems, and languages, that allow large numbers of microprocessors to be interconnected to cooperate in the solution of large, complex, computational problems. Since late 1994, I have been involved in the application of these high-performance computing technologies to the specific problem domain of the Human Genome Project. My efforts, in collaboration of members of the College of Medicine, have involved the design of networked systems of computers to analyze large amounts of genetic sequence data taken from mixed tissue libraries of variably expressed mRNA transcripts. Further, processing of this data has required extensive computation to construct genetically anchored maps showing relative locations of all genes. Finally, we have constructed web-based tools to collect, organize, and analyze genetic marker data, pedigree and clinical data to identify linkage between gene candidates and specific diseases including hypertension, obesity, glaucoma, and autism.

Research Modes

Computational

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways, Chromatin and Histone Modifications, DNA Methylation and Epigenetics, Gene-environment Interactions and Interplay, Genetic Association Studies, Genetic Engineering, Machine Learning, MiRNA and Post-transcriptional Regulation, Mutation, Network and Systems Biology, Non-coding RNA, Population Genetics, Protein Folding and Structure, Protein-protein Interactions, Sequencing and Variant Detection, Splicing, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Behavior and Mental Disorders, Cancer, Cardiovascular System, Development and Dysmorphology, Endocrine System, Evolution and Phylogeny, Eye and Vision, Hearing, Immune System, Metabolism and Nutrition, Microbiome and Infectious Diseases, Orthopaedics, Public Health and Epidemiology, Respiratory System, Stem Cells

Organisms

Bovine, C. Elegans, Drosophila, Human, Microbial and Viral, Rodent (mouse/rat), Yeast and Fungi, Zebrafish
Chi-Lien  Cheng Ph.D.
Associate Professor
Biology

 

Alternation of generations in land plants; Vegetative phase change in maize

All land plants progress through a life cycle that alternates between two multicellular generations, the haploid gametophyte and the diploid sporophyte. In ferns, seedless vascular plants of the Monilophyte clade, both generations are free living.  In addition to the normal life cycle using meiosis to generate spores and sexual union to form zygotes, in nature many fern species can switch from one generation to another asexually.  In the asexual pathways, a gametophyte is generated from sporophytic cells without meiosis and a sporophyte is generated from gametophytic cells without fertilization, respectively.  The model fern Ceratopteris richardii does not reproduce asexually in nature but both pathways can be induced in the laboratory using specific culture conditions.  The independence of the two generations in ferns and the ease of switching from one generation to the other through the asexual pathways offer a system suitable for studying how each generation is initiated.  This developmental plasticity of crossing generation barriers, i.e., meiosis and fertilization, is not unique to ferns and is manifested in the complex pathways leading to apomixis in some seed plants. My lab has identified genes potentially important in the asexual pathways in C. richardii.  We are interested in learning how the functions of these genes are evolved between the fern and the seed plant Arabidopsis.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Mutation, Transcription and Transcriptional Regulation

Applications

Evolution and Phylogeny, Stem Cells

Organisms

Plant
Josep M Comeron Ph.D.
Associate Professor
Biology

We apply a multidisciplinary approach-combining empirical work to obtain sequence data, large-scale genomic analyses, and the development of theoretical, analytical and computational tools-to investigate: 1) variation in the efficacy of natural selection among species and across genomes, 2) the evolution of recombination across genomes and among species, 3) the evolution of introns (presence and size) and genome structure in eukaryotes, 4) the evolutionary consequences of changes in population size, and 5) the genetic basis of speciation. Likely, many mutations important to evolution have much smaller selection coefficients than it is practicable to demonstrate in the laboratory. Population genetics and molecular evolution analyses-the study of nucleotide variability within and between species, respectively-are powerful tools that allow us to detect the action of selection on naturally-occurring mutations, even if the fitness effects of these mutations are extremely weak. We study the causes and consequences of changes in recombination rates among species and across genomes, focusing on the influence of meiotic recombination on the efficacy of selection in eukaryotes. To measure possible changes in the effectiveness of selection, we study weakly selected mutations such as synonymous mutations (changes in the coding sequence that do not alter protein sequence) and small insertion/deletions (indels). The same population genetics techniques that are commonly applied to nucleotide changes can be also applied to genomic features, allowing us to investigate the forces involved in the evolution of gene number, the origin of introns, the evolution of exon-intron structures, and ultimately genome size. This genomics-meets-population genetics approach (i.e., population genomics) can be implemented with computer simulations mimicking the evolutionary process (in silico evolution), a computationally-intensive technique that provides new and valuable insights into the expected outcome of complex evolutionary processes. We also apply molecular evolution and population genetics techniques to study recent speciation events. In particular, we investigate Drosophila species to gain insight into the evolutionary patterns of genes involved in phenotypic differentiation and reproductive isolation.

Research Modes

Computational, Experimental

Research Paradigms

DNA Methylation and Epigenetics, Gene-environment Interactions and Interplay, Mutation, Network and Systems Biology, Population Genetics, Sequencing and Variant Detection

Applications

Evolution and Phylogeny, Genomics

Organisms

Drosophila
Robert A Cornell Ph.D.
Professor
Anatomy & Cell Biology

The neural crest, a transient population of multi-potent precursor cells exclusively found in vertebrate embryos, gives rise to neurons, glia, and melanocytes, among other cell types. The neural crest is thus an attractive model in which to explore universal cellular developmental events like fate specification, migration, survival, and differentiation. Moreover, when these events go wrong in neural crest there can be dire consequences for the individual, including cleft lip and palate, neuroblastoma, neurofibromotosis, and melanoma. We strive to identify the gene products that regulate developmental decisions within the neural crest. Better knowledge of these genes will improve the ability of clinicians to predict the likelihood of an individual to succumb to such diseases. Moreover, developmental regulatory genes represent potential therapeutic entry points for a wide range of diseases. We use forward and reverse genetics methods in zebrafish towards this end. http://www.anatomy.uiowa.edu/pages/directory/faculty/cornell.asp

Research Modes

Experimental

Research Paradigms

DNA Methylation and Epigenetics, Developmental Genetics, Genetic Engineering, Network and Systems Biology, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology, Evolution and Phylogeny, Nervous System

Organisms

Zebrafish
Ben  Darbro M.D., Ph.D.
Assistant Professor, Director of the Shivanand R. Patil Cytogenetics and Molecular Laboratory
Pediatrics

My primary research interest is in the genetic determinants of intellectual disability (ID), formerly referred to as mental retardation (MR).  I specifically study the roles of copy number variation and somatic structural variation in the context of a “genomic mutational burden” hypothesis of ID.  This hypothesis is investigated using a combination of conventional cytogenetics methods (chromosome analysis and fluorescence in situ hybridization) and new molecular, high throughput, and high data volume, genomic technologies including single nucleotide polymorphism (SNP) arrays, gene expression microarrays, comparative genomic hybridization (CGH) arrays as well as custom targeted, whole exome, and whole genome massively parallel DNA sequencing.  We perform all our own bioinformatics and are actively engaged in the development of new analysis tools to better meet our needs and those of the scientific community.  Drosophila melanogaster and the well-established GAL4/UAS/RNAi system are used to evaluate candidate ID genes with the use of a validated olfaction learning technique (T-Maze).  Candidate genes are derived from our extensive clinical database of patients with ID that have already undergone diagnostic chromosomal microarray testing.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways, Genetic Association Studies, Mutation, Network and Systems Biology, Sequencing and Variant Detection

Applications

Behavior and Mental Disorders, Cancer, Development and Dysmorphology, Immune System, Nervous System

Organisms

Drosophila, Human
Deborah V Dawson Ph.D., Sc.M.
Professor
Pediatric Dentistry

My research interests focus on human genetic disorders, including both the development of new statistical methods for their investigation, and applied studies. My methodological research has included development of techniques in the areas of delayed onset disorders and correction for ascertainment bias, as well as approaches to problems in population immunogenetics, most recently as they relate to vaccine research. My applied work includes statistical genetic modeling of human disorders, and biostatistical modeling related to other clinical and epidemiologic studies. Modeling activities have focused on the genetics of the human major histocompatibility (HLA) complex, immune and inflammatory disorders (including autoimmune disorders and periodontal disease), and developmental disorders. The latter include studies of Fragile X syndrome, and genetic syndromes affecting teeth and bone. Other areas of application include studies related to craniofacial development, including longitudinal studies of normal development, and investigations of late onset disorders and of aging, including the genetics of longevity. More recent interests include the analysis of microarray data, meta-analytic assessment, and classification and risk assessment problems, particularly as they relate to genetic counseling.

Research Modes

Computational

Research Paradigms

Gene-environment Interactions and Interplay, Genetic Association Studies, Population Genetics

Applications

Behavior and Mental Disorders, Development and Dysmorphology, Microbiome and Infectious Diseases, Public Health and Epidemiology

Organisms

Human
Arlene V Drack M.D.
Associate Professor
Ophthalmology

Arlene V. Drack, M.D. is a clinician scientist specializing in juvenile inherited eye diseases.  She is the inaugural Ronald V. Keech Associate Professor in Pediatric Ophthalmic Genetics at the University of Iowa Department of Ophthalmology and Visual Sciences.  Her research focuses on inherited eye diseases that affect children, particularly in the development of novel treatments.  She is experienced in subretinal injection of molecules to treat mouse models of retinal degeneration, as well as participating in human trials for retinal disorders.  Her laboratory is investigating gene therapy and other treatments in mouse models of Bardet Biedl Syndrome and other retinal degenerations.  She is also active in investigations of human PAX6 mutations and disease mechanisms in pediatric retinal degeneration.  She co-directs both the clinical and rodent electroretinogram services at the University of Iowa.  Her clinical practice includes the full scope of pediatric ophthalmology and strabismus, in addition to running specialized genetic eye disease clinics.

Research Modes

Not applicable

Research Paradigms

Gene Therapy, Genetic Engineering

Applications

Eye and Vision

Organisms

Human, Rodent (mouse/rat)
Adam J Dupuy Ph.D.
Associate Professor
Anatomy & Cell Biology

Human cancers arise through a multi-step genetic process that involves the loss of tumor suppressor genes and activation of proto-oncogenes. However, it is challenging to identify the causal mutations amid the large number of genetic and epigenetic changes typically found in human tumors. Mouse models of human cancer have been useful in testing the contribution of specific mutations in oncogenesis. Unfortunately, single gene mouse models often do not translate well when compared to human cancer. It is thought that these models lack a sufficient number of mutations to generate aggressive tumors typically seen in human cancer patients. Insertional mutagenesis provides many advantages over single gene mouse models. The most common insertional mutagen used in mouse models of cancer is the murine leukemia virus. In these models, retroviral infection of hematopoietic cells leads to mutation when the provirus integrates into the host cell genome. Several rounds of retroviral infection followed by clonal expansion eventually leads to the development of leukemia/lymphoma in the mouse. This multi-step process is similar to what occurs in human cancer and produces tumors that are genetically heterogeneous. In retrovirally-induced tumors the provirus marks the site of mutation and provides a sequence tag that can be used to efficiently identify the mutated genes. Several labs have identified over 150 candidate cancer genes by cloning more than 2,000 proviral integrations sites from a variety of retrovirally-induced mouse models of leukemia and lymphoma (available at http://genome2.ncifcrf.gov/RTCGD). Unfortunately, retroviral infection of mice produces mammary and hematopoietic malignancies primarily. However, Sleeping Beauty (SB), an engineered cut-and-paste transposon system, has demonstrated activity in a variety of tissues in the mouse. The system consists of two parts—the transposase enzyme provided in trans and the DNA transposon vector. When these elements are present in the same cell, SB transposase binds to sites in the transposon and mediates excision from the donor site and integration to a random TA dinucleotide in the genome. Previous work has shown that transposons can generate de novo mutations when they integrated into the mouse genome. Recent work has modified the SB system as a somatic cell mutagen to induce tumor formation in mice. This work describes the first nonviral insertional mutagen capable of inducing tumors in vivo. In this regard, SB has several advantages over retroviruses in their ability to perform screens for cancer genes mainly because SB mutagenesis can be controlled by simply by regulating SB transposase expression. Current efforts are focused on generating tissue specific models of cancer in mice by directing transposase expression to specific sites in the mouse.

Research Modes

Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, Gene-environment Interactions and Interplay, Genetic Engineering, Mutation, Network and Systems Biology, Sequencing and Variant Detection, Translation and Post-translational Modifications

Applications

Ageing, Cancer

Organisms

Human, Rodent (mouse/rat)
Professor
Biology
We are interested in molecular and cellular mechanisms of how organisms detect sounds, and how they use information from sounds to direct their behavior. Drosophila males sing the "love song" to females by wing vibration. Females and males both hear the love song with their antennae and respond in a sex-specific manner. Using Drosophila, we can combine genetics with electrophysiology and behavior to dissect hearing mechanisms. We have identified mutants that no longer respond normally to the love song. The beethoven mutant disrupts the electrophysiology of Johnston's organ, the mechanoreceptive organ in the antenna responsible for hearing. Identifying the gene product of beethoven and other such genes and examining their functional roles in hearing will provide new insights into auditory molecular mechanisms in Drosophila, and perhaps in humans as well. We also want to understand how organisms decipher the meaning in auditory information, and how males and females can respond differently to the same sounds. Therefore, we want to study firing patterns in the sensory neurons, and neuronal circuitry by which the brain decodes these patterns into motor outputs. Finally, we want to determine if any sounds can evoke other behaviors such as escape from predators.

Research Modes

Experimental

Research Paradigms

Gene-environment Interactions and Interplay, Genetic Engineering, Imaging, Mutation, Network and Systems Biology, Protein-protein Interactions, Sequencing and Variant Detection

Applications

Hearing, Nervous System

Organisms

Drosophila
Craig D Ellermeier Ph.D.
Associate Professor
Microbiology

Cells often respond to changes in their environment by altering gene expression. My research focuses on understanding the basic molecular mechanisms involved in how cells sense and respond to extracellular signals. We are specifically interested in mechanisms of signal transduction in response to cell envelope stresses in Gram positive bacteria. Our studies focus on the transcriptional responses of bacterial cells to a novel antimicrobial peptide SdpC.  We have identified two novel signal transduction systems from B. subtilis which sense and respond to this antimicrobial peptide. The first of these is a signal transduction system which utilizes a membrane protein, SdpI, to sequester a repressor and inhibit its activity. This increases expression of SdpI which also provides resistance to the antimicrobial peptide. The second pathway we have identified activates an alternative sigma factor, σW. The σW factor is activated by proteolytic destruction of the membrane-bound anti-σW by successive proteolytic events known as Site-1 and Site-2 cleavage. We identified a multi-pass membrane protein called PrsW that is required for Site-1 cleavage of anti-σW. Interestingly these systems are conserved in the emerging opportunistic pathogen Clostridium difficile. We are investigating the role of these signal transduction systems in C. difficile virulence.

Research Modes

Experimental

Research Paradigms

Gene-environment Interactions and Interplay, Protein Folding and Structure, Protein-protein Interactions, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Microbiome and Infectious Diseases

Organisms

Microbial and Viral
Albert J Erives Ph,D.
Associate Professor
Biology

The Genetics of Eukaryotic Transcriptional Enhancers

Transcriptional enhancers are DNA sequences that specify inducible, spatiotemporal patterns of gene expression at most gene loci. Several complementary results from genomic studies have shown that the majority of functional sites in a genome correspond to transcriptional enhancer sequences, thus underscoring their importance for understanding basic physiology. However, while transcriptional enhancers represent a major class of regulatory DNAs in eukaryotic genomes, the entire set of sequences that are necessary and sufficient for constructing a complex eukaryotic enhancer are not yet known.

Our laboratory is focused on using molecular biology, genomics, bioinformatics, and transgenic model systems to understand enhancer biology. A major area of focus in our laboratory is the study of how different morphogen-concentration specific responses are encoded at different loci. We are also interested in understanding the sequence-function relationship well enough to understand the complex patterns of molecular evolution occurring at enhancer sequences.

Research Modes

Computational, Experimental

Research Paradigms

Chromatin and Histone Modifications, Population Genetics, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology, Evolution and Phylogeny

Organisms

Drosophila
Jan S Fassler Ph.D.
Professor
Biology

S. cerevisiae is an important model for the study of environmental stress responses. My interest has been in probing the influence of the environment on the physical characteristics of cells by studying adaptive changes in transcription. All cells have the capacity to precisely modulate the transcriptome, changing the levels at which specific genes are expressed in order to ensure survival in the face of specific challenges or changes in the environment. The response to oxidative stress is critical for preserving cellular integrity in an aerobic environment. Cellular damage resulting from oxidative stress has been implicated in normal cellular processes such as apoptosis, and aging as well as in a host of pathological conditions from Down\'s syndrome to cancer. The S. cerevisiae transcription factors Yap1p and Skn7p directly trigger activation of many of the OSR (oxidative stress response) target genes. Although activation of Yap1p upon oxidative stress has been extensively investigated, little is known about the activation of Skn7p during this process. Our preliminary work on this subject identified several threonine residues in the Skn7 receiver domain as likely phosphorylation sites and showed their importance in the interaction with Yap1p. We are also interested in the identification and characterization of molecules contributing to the oxidative stress responsiveness of Skn7p. Finally, we plan to investigate the hypothesis that Skn7p may play a specific role in sensing and responding reactive oxygen species generated in the mitochondria. In addition to oxidative stress, fluctuation in the external osmotic environment is a common challenge for cells. The molecular mechanism of osmotic stress sensing has important health implications in higher organisms where osmolality is closely linked not only to kidney medulla function, but also to vascular volume, levels of cardiac output and arterial pressure. Extensive parallels between the yeast and mammalian stress activated MAP kinase pathways suggest that yeast based insights into the molecular mechanism of osmotic stress signal transduction are likely to be general. The yeast stress-activated MAP kinase pathway responsible for osmosensing is regulated by Sln1. The activity of Sln1p is diminished in response to hypertonic stress and increased in response to hypotonic stress. Bifurcation of the pathway downstream of Sln1p leads to distinct stress-specific reprogramming of gene expression; hypertonic conditions lead to accumulation of compatible solutes via a p38 like MAP kinase cascade, whereas hypotonic conditions elicit changes in cell surface properties by direct aspartyl phosphorylation of the Skn7 transcription factor. Our work focuses on understanding how Sln1p interacts with its subcellular environment to sense and respond to changes in the external milieu; determining how phosphorylation of the SLN1-dependent transcription factor, Skn7p leads to specific activation of osmotic response genes; and characterizing the division of labor and/or overlap between the SLN1-SKN7 and the PKC cell wall integrity pathways in their efforts to ensure cellular integrity. Characterizing the mechanics of the yeast Sln1p sensor-kinase is likely to contribute new perspectives on the process by which eukaryotic cells maintain osmotic homeostasis.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Genetic Engineering, Mutation, Protein Folding and Structure, Protein-protein Interactions, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Cancer, Cardiovascular System, Microbiome and Infectious Diseases

Organisms

Yeast and Fungi
John H. Fingert M.D., Ph.D.
Professor
Ophthalmology and Visual Sciences

My laboratory studies the molecular genetic basis of glaucoma and other inherited eye diseases using a range of patient-based research techniques. We have focused our genetic research on glaucoma because this condition is a leading cause of blindness and visual disability worldwide and there is a strong genetic component to its pathogenesis. My laboratory has ongoing projects to identify new glaucoma genes using both pedigree-based positional cloning approaches and population-based association studies. We are also conducting population-based studies of intraocular pressure and other quantitative traits of glaucoma including investigations to identify the genetic basis of patient response to drugs (pharmacogenomics). The ultimate goal of our research is to translate laboratory investigations into useful genetic tools for clinicians by developing genetic tests and providing insights needed for the development of the next generation of therapies to help prevent blindness.

Research Modes

Experimental

Research Paradigms

Imaging, Mutation, Protein-protein Interactions, Sequencing and Variant Detection

Applications

Eye and Vision

Organisms

Human, Rodent (mouse/rat)
C. Andrew  Frank Ph.D.
Assistant Professor
Anatomy and Cell Biology

Homeostasis is a robust form of regulation that allows a system to maintain a constant output despite external perturbations. In the nervous system, homeostasis plays a critical role in regulating neuronal and synaptic activity. Yet the molecular basis of this form of neural plasticity is generally unknown. We address this problem using the fruit fly, Drosophila melanogaster.  This model allows us to combine electrophysiology with powerful genetic and pharmacological techniques. The overall goal is to define conserved signaling mechanisms that direct synapses to maintain stable properties, like excitation levels.

It is generally believed that molecules controlling the balance of excitation and inhibition within the nervous system influence many neurological diseases. Therefore, understanding synaptic homeostasis is of clinical interest. This area of research could uncover factors with relevance to the cause and progression of disorders such as epilepsy, which reflects a state of poorly controlled neural function.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation, Network and Systems Biology, Neurogenetics, Protein-protein Interactions

Applications

Behavior and Mental Disorders, Development and Dysmorphology, Nervous System

Organisms

Drosophila
Pamela  Geyer Ph.D.
Professor
Biochemistry

The eukaryotic nucleus is highly organized to facilitate the regulation of gene expression. This organization includes the localization of chromosomes into discrete nuclear territories that are enriched in different classes of transcription factors, as well as the definition of independent structural domains within chromosomes that constrain interactions between transcriptional control elements and target promoters. To understand these processes, our laboratory uses Drosophila melanogaster as a model organism, employing multi-dimensional experimental approaches that include genetics, biochemistry and molecular biology. Two major research areas are represented in the laboratory. First, we investigate how proteins located in the nuclear envelope and underlying lamina contribute to chromosome organization and gene expression. Second, we study the properties of DNA elements called insulators that are used to define independent structural and functional domains within chromosomes.

The nuclear lamina is an extensive protein network comprised of lamins and several classes of lamin interacting proteins. Our studies focus on the family of LEM domain proteins that share a protein interaction domain that establishes a link between the nuclear lamina and chromosomes. Alterations in LEM domain proteins cause several human diseases, including Emery-Dreifuss muscular dystrophy and Buschke-Ollendorf syndrome. Mechanisms responsible for these diseases are intriguing as these nuclear lamina proteins are globally expressed, yet pathologies are often tissue-specific. We are determining the role of the LEM domain proteins in regulation of genes involved in tissue differentiation and development. Our studies will provide insights into the molecular mechanisms contributing to human diseases associated with laminopathies.

Insulators are a conserved class of DNA elements that define chromatin domains of independent gene function. Insulators block interactions between enhancers and silencers when placed between these elements and a promoter. This property suggests that insulators are favorable candidates for improving the design of gene therapy vectors, as insulators have the ability to prevent cross-regulatory interactions between vector genes and the regulatory elements in the host genome. Our studies are directed at identifying novel insulators and defining the molecular mechanism by which insulators establish independent functional domains.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology

Organisms

Drosophila
Chad E Grueter Ph.D.
Assistant Professor
Internal Medicine

Our laboratory studies transcriptional processes that are disrupted in disease. We identified a novel transcriptional signaling pathway in the heart that mediates the heart’s ability to regulate whole body metabolism. Through a combination of pharmacological and genetic gain- and loss-of-function studies in mice, we found the heart is capable of regulating whole body metabolism through a mechanism that is governed by MED13 and miR-208a. MED13 is a particularly interesting component of the Mediator complex because it functions as a molecular bridge between the core complex and kinase submodule, providing a mechanism for spatial and temporal control of Mediator-dependent regulation of transcription. In addition, we are studying the function of multiple components of Mediator including CDK8, CDK19, MED12 and CycC. We primarily utilize mutant mouse models to study the proteomic, molecular, bioinformatic and biochemical methods to study the molecular signaling events controlling cardiac response to stress.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, DNA Methylation and Epigenetics, Genetic Engineering, Mutation, Network and Systems Biology, Non-coding RNA, Protein-protein Interactions, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Cardiovascular System, Metabolism and Nutrition

Organisms

Rodent (mouse/rat)
Shizhong  Han Ph.D.
Assistant Professor
Psychiatry

We aim to dissect the genetic components of psychiatric disorders using cutting-edge genomic technologies, advanced statistical genetic methods, and multidisciplinary approaches. In addition to gene mapping efforts for psychiatric disorders, we are also interested in developing novel statistical methods and computational tools to meet the challenges arising from large-scale genetic and genomic data.

 

 

Research Modes

Computational, Experimental

Research Paradigms

Genetic Association Studies, Network and Systems Biology, Sequencing and Variant Detection

Applications

Behavior and Mental Disorders, Nervous System

Organisms

Human
Douglas W Houston Ph.D.
Associate Professor
Biology

My research is focused on one of the central problems in developmental biology: how a single-celled egg differentiates into an organism containing many different cell and tissue types. Because changes in the activity of genes controlling early development are known to cause human birth defects, disease and infertility, it is important to understand how these genes function in normal embryos. To address this issue, we use the frog Xenopus laevis as a model organism. Frog embryos develop outside the female, and can be cultured in simple media, allowing experimental manipulation of the early stages of development. Current research centers on understanding how RNAs and proteins, differentially localized within the egg, contribute to directing early cell differentiation. These \"maternal factors\" are anchored to one pole of the egg, and are responsible for three major processes: (1) specification of the primordial germ cells (PGCs), the stem cell-like precursors of the gametes; (2) induction and patterning of the ectoderm, mesoderm and endoderm (the primary germ layers), the main divisions of tissue types in animals; and (3) establishment of the dorsal body axis, including the central nervous system. Recently, we used microarray analysis to identify mRNAs localized to the vegetal cortex, a cytoskeleton-rich layer beneath the plasma membrane on the vegetal (unpigmented) side of Xenopus eggs. We isolated numerous novel genes with potential roles in each of the above pathways, including genes involved in PGC formation, morphogenesis, and TGF-beta and Wnt growth factor signaling. Possible projects in my lab would include the functional characterization of these new genes using embryological and cell biological techniques in Xenopus, such as microinjection, antisense depletion of maternal mRNAs, gene expression analysis and studies of morphogenesis.

Research Modes

Experimental

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways

Applications

Development and Dysmorphology, Nervous System

Organisms

Xenopus Laevis
Erin E Irish Ph.D.
Associate Professor
Biology

Our lab is interested in the genetic and cellular mechanisms by which a plant develops its morphology. Plants have the ability to continue to initiate and differentiate new organs throughout their life. This is accomplished through the activity of meristems. An interesting paradox is that, despite the presence of apical meristems, plant shoots often exhibit a determinate pattern of growth, both in vegetative and reproductive portions. Questions that research in our lab addresses include: What mechanisms determine the fate of a meristem to be determinate vs. indeterminate? vegetative vs. floral? What is the signal that limits meristem activity? One project in our lab concerns the regulation of the extent of vegetative development by the shoot meristem of maize, a day-neutral plant. We are able to culture isolated maize shoot apical meristems. This manipulation has allowed us to determine that the developmental program that regulates meristem activity is not contained within the meristem, but must act by the signaling of the meristem from some other portion of the plant. Using this approach we have shown that leaves are the source of the signal, and that relatively young leaves are capable of providing the signal. A second project in our lab focuses on determinacy of reproductive meristems. We have found that this process involves genes that are also crucial for normal sex determination. This suggests that sex determination functions were evolved from genes whose ancient function was to control determinacy in reproductive meristems. These genes, called tassel seed, when mutant feminize the plant by causing female rather than male flowers to form on the tassel. Genetic and molecular approaches are being taken to ask how pistils are suppressed in the tassels of normal maize plants. We are using transposon tagging methods to isolate molecular probes for these genes, with the goal of elucidating the role of tassel seed genes on meristem function and sex determination.

Research Modes

Experimental

Research Paradigms

Developmental Genetics, Mutation, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology

Organisms

Plant
Wayne A Johnson Ph.D.
Professor
Molecular Physiology & Biophysics

Somatosensory signaling is the process by which we become aware of external sensations such as touch, temperature or pain. Despite the importance of these sensory modalities to our everyday existence, we know relatively little about their molecular mechanisms. These sensations would appear to be quite different, however, recent work has shown that they may be separated by only a fine line at the molecular level. Two large ion channel families, the TRP channels and the ENaCs, appear to have been evolutionarily selected for a variety of physiological functions ranging from thermosensation and osmosensation to pain and touch. We have developed a genetic model system in Drosophila to examine the molecular components of somatosensory signal transduction in type II multiple dendritic(md) sensory neurons. We are applying a variety of techniques including electrophysiology, behavior, molecular biology and genetics to identify and characterize evolutionarily conserved signaling components.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Genetic Engineering, Imaging, Mutation, Network and Systems Biology, Transcription and Transcriptional Regulation

Applications

Immune System, Nervous System

Organisms

Drosophila
Brad D Jones Ph.D.
Professor
Microbiology

The objective of the research in my laboratory is to elucidate the pathogenic mechanisms of Salmonella species. One important pathogenic attribute of Salmonella species is their ability to enter mammalian cells. The ability of these bacteria to invade host cells is controlled by a variety of environmental signals that control invasion gene expression. We have performed a variety of genetic screens to identify genes that control the expression of the Salmonella invasion machinery. Those experiments have revealed that the regulatory pathways use two-component signaling systems, known small DNA-binding proteins, and Salmonella-specific proteins. A variety of research projects are underway to characterize these pathways in detail and to explore how regulation of this particular virulence property is integrated into the control of the entire pathogenic strategy of the organism as well as to discover how virulence gene expression is managed within the context of bacterial physiology. This work as provided significant insights into the bacterial-host cell interactions that allow these bacteria to survive and grow within the lymphatic system of mammalian hosts. A second project in the laboratory, which has been recently funded, is a characterization of the virulence factors of Francisella tularensis. This potential bioweapon is a significant pathogen which causes a systemic infection similar to the \"plague\" caused by Yersinia pestis. Work is being initiated to characterize the adherence, invasive, and intracellular survival properties of this organism as well as to develop genetic tools for manipulation and study of the bacteria.

Research Modes

Experimental

Research Paradigms

Genetic Engineering, Imaging, Mutation, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Cardiovascular System, Immune System, Microbiome and Infectious Diseases, Respiratory System

Organisms

Microbial and Viral, Rodent (mouse/rat)
Toshihiro  Kitamoto Ph.D.
Associate Professor
Anesthesia and Pharmacology

How does the nervous system control complex behavior? How do experience and genetic variation modify it? The goal of our research is to answer these fundamental questions in neuroscience. We use the fruitfly, Drosophila melanogaster as an experimental animal, and integrate knowledge of the nervous system at the molecular, cellular, systemic and whole animal levels. The current focus is on male courtship behavior. This behavior consists of a highly stereotypical sequence of activities that are genetically determined, but also shows considerable experience-dependent plasticity called \"courtship conditioning\". By examining the behavior of various genetic variants, we study the function of particular genes in different aspects of courtship. In addition, using a recently developed strategy that allows one to perturb synaptic transmission rapidly and reversibly in a spatially restricted manner in intact animals, we investigate the significance of particular neuronal subsets in sexual orientation, courtship initiation, and courtship memory. Our multidisciplinary research is expected to provide new insights into the basic mechanisms underlying higher-order brain functions that control complex behavior.

Research Modes

Experimental

Research Paradigms

Gene-environment Interactions and Interplay

Applications

Behavior and Mental Disorders, Nervous System

Organisms

Drosophila
Aloysius J Klingelhutz Ph.D.
Associate Professor
Microbiology

In the broadest sense, my goal is to understand the biology and genetics of human cancer and aging. One of my primary interest is in how epithelial cells become immortal and subsequently malignant after infection with human papillomavirus (HPV). We are specifically focusing on the roles of genetic instability and telomerase activation in this process. I also am studying how telomere loss and other factors are involved in induction of cellular senescence. Specific areas of research are the following: 1) Defining the roles of telomere loss and telomerase dysfunction in keratinocyte aging and transformation; 2) Examining the regulation of cellular genes by HPV E6 and E7 during the process of infection and transformation; 3) Establishment and utilization of relevant model systems to study HPV-associated immortalization and malignant progression of human epithelial cells; 3) Defining mechanisms of genetic instability and determining the role of specific genomic alterations in the development of head and neck cancers; 5) Determining how the cell cycle inhibitor, p16INK4a, is regulated during telomere-independent senescence of human epithelial cells. It is hoped that these studies will increase our understanding of the processes that cause cancer and aging and will lead to better methods to prevent, diagnose, and treat human disease.

Research Modes

Experimental

Research Paradigms

Cell Cycle/replication/recombination, DNA Methylation and Epigenetics, Genetic Engineering

Applications

Ageing, Cancer, Metabolism and Nutrition, Microbiome and Infectious Diseases

Organisms

Human
Markus H Kuehn Ph.D.
Associate Professor
Ophthalmology and Visual Sciences

My laboratory studies genetic factors that underlie or contribute to optic neuropathies - in particular glaucoma and the neurodegeneration associated with idiopathic intracranial hypertension (IIH).  Data from our studies have shown that components of the complement system are synthesized in the retina in glaucoma and that activation of complement accelerates retinal ganglion cell death.  In addition, variations in certain complement component genes appear to be associated with glaucoma.  A second area of interest is IIH.  The genetics of this condition and the cellular events that result in the degeneration of the retina are poorly understood. We are currently involved in a study designed to determine which genes are involved in the regulation of intracranial pressure and if certain genotypes are correlated with the development of the disease in human patients.

Research Modes

Clinical, Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Association Studies, Mutation, Population Genetics

Applications

Development and Dysmorphology, Eye and Vision

Organisms

Human
Anne E Kwitek Ph.D.
Associate Professor
Pharmacology

Common human diseases such as hypertension, diabetes and obesity can lead to serious complications such as heart attacks, congestive heart failure, kidney failure and early death. Both environmental and genetic factors contribute to these complex (multifactorial) diseases. Identifying their genetic component(s) will lead to better understanding of their dysfunctional mechanisms and improve our ability to prevent or more effectively treat their complications.

My laboratory uses physiological and comparative genomic approaches to identify genes and mechanisms leading to complex disease - hypertension, diabetes and obesity in particular - using both rat models and human populations. We use genetic linkage strategies to genetically map genes, and genetically unique rat strains to positionally clone and/or test candidate genes within a specific region of the genome. We then compare the genomes between the species, via comparative genomics, to translate the data from the rat to human and back again. Because the rat and human genes are 90% identical, it is likely the same genes or pathways will also play a role in many diseases.

Research Modes

Computational, Experimental

Research Paradigms

Genetic Association Studies, Network and Systems Biology, Population Genetics, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Cardiovascular System, Drugs and Pharmacogenomics, Endocrine System, Metabolism and Nutrition

Organisms

Rodent (mouse/rat)
Bridget Lear Ph.D.
Assistant Professor
Biology

My lab is interested in understanding the neural mechanisms that regulate circadian rhythms, the daily patterns of physiology and behavior that are prominent in many species.  We study the model system Drosophila, whichexhibits robust daily rhythms in several behaviors, including locomotor activity.  Genetic approaches in Drosophila have led to the identification of a number of key circadian rhythms genes, including several with conserved function in mammals.  Much of this research has focused on understanding the molecular circadian clock, the cell-autonomous transcriptional feedback loops and post-translational modifications that generate ~24 hour molecular oscillations.  In Drosophila and mammals, the central circadian clocks that control rhythmicity are located in neuronal groups within the brain. Yet, little is known about how the molecular clock regulates the output of these neurons to promote rhythmicity.  We are interested in understanding the processes that occur downstream of the molecular clock to mediate circadian neuron function. I have previously demonstrated that a putative sodium leak channel, narrow abdomen (na), is an important component of circadian neuronal output in Drosophila. We are now using this system to further characterize the function and regulation of this unique channel, with a particular interest in determining whether NA is subject to circadian regulation. In addition, my lab is utilizing the molecular and genetic tools of Drosophila in order to identify new circadian rhythms genes, with a focus on genes likely to function in circadian neuronal output.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation, Network and Systems Biology, Protein-protein Interactions, Translation and Post-translational Modifications

Applications

Behavior and Mental Disorders, Nervous System

Organisms

Drosophila
Fang  Lin M.D., Ph.D.
Assistant Professor
Anatomy & Cell Biology

Diverse cell movements play critical roles in early embryonic development and organogenesis, as well as in proper organ function and homeostasis later in life. G protein signaling is one of the molecular genetic mechanisms that control these processes, and we are using zebrafish as a model system in which to investigate the roles of various G proteins during embryogenesis. Zebrafish is an excellent animal model for the analysis of morphogenetic cellular behaviors in the context of a developing embryo because the externally development and optical clarity of the embryos, in combination with well-established GFP lineage tracing techniques, makes it easy to monitor individual cells throughout development. Moreover, it is possible to generate large numbers of mutant and transgenic fish lines, as well as to manipulate gene activity in this system. My current projects include: 1) understanding the involvement of G protein signaling pathways in the migration of primordial germ cells (PGC); 2) investigating the roles of G protein signaling in gastrulation movements; and 3) elucidating the functions of Gbg/PI3Kg in neutrophil migration.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation

Applications

Cardiovascular System, Development and Dysmorphology

Organisms

Zebrafish
Ana Llopart Ph.D.
Associate Professor
Biology

In our laboratory we seek to understand the evolution of the genetic barriers responsible for species being reproductively isolated from one another; ultimately the genetic basis of speciation. Today we know that these barriers often involve genic incompatibilities among alleles that function normally in their usual genetic background and produce perfectly fit genotypes, but generate hybrid dysfunction (i.e. sterility and inviability) when encounter alleles from other species. 

To gain insight into the evolution of these genetic barriers we study hybrids where incompatibilities become apparent. Our approaches use methodologies that combine classic genetics, modern genomics and population genetics, and an ideal biological system of two very closely related species of fruit flies, Drosophila yakuba and D. santomea, which produce abundant hybrids in nature.

One of our current areas of research is centered on studying the genetic basis of sterility of female hybrids between D. yakuba and D. santomea. Hybrid female sterility is a trait that has been a bit more neglected than that of their counterparts hybrid males. In this system, sterility involves at least one factor of recent evolution in D. yakuba that is placed in the cytoplasm of the hybrid embryo and that is incompatible with D. santomea genes. We are also interested in evaluating natural introgression, that is, the effective exchange of genes between species through rare hybridization in nature. Experiments in the laboratory can be very useful to detect genomic regions associated with isolating barriers, but they seldom capture the full complexity of nature. By identifying genes that are able to transgress species boundaries in the natural habitat we can built introgression landscapes, which allow us to gain valuable insights into the chromosomal location of genes either responsible for local adaptation or involved in hybrid dysfunction. Our third on-going project focuses on a very special type of genic incompatibilities, those between cis-regulatory sequences of genes and transcription factors. Independent evolution of these two interacting components involved in transcription regulation in different species usually leads to breakdown of gene expression in hybrids.

Research Modes

Computational, Experimental

Research Paradigms

Cell Cycle/replication/recombination, Population Genetics, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Evolution and Phylogeny

Organisms

Drosophila
John  Logsdon Ph.D.
Associate Professor
Biology

The Logsdon lab works on a variety of related topics in molecular evolutionary genetics:

SEX & MEIOSIS:

  1. Exploring the origin and evolution of meiotic genes in diverse eukaryotes.
  2. Molecular evolution and phylogeny of meiotic genes.
  3. Isolation of meiosis-related genes from protists and other eukaryotes.
  4. Functional studies of meiotic genes isolated from diverse eukaryotes.
  5. Bioinformatic studies of meiosis and recombination/repair genes.

TREES:

  1. Understanding the molecular phylogeny of eukaryotes.
  2. Using complex gene families to root the eukaryotic tree of life.
  3. Isolating new protein genes to address thorny issues in eukaryotic phylogeny.

LATERAL GENE TRANSFER:

  1. Developing a better understanding of the frequency, roles, distribution and phylogenetic impacts of LGT in prokaryotes.
  2. Comparative bioinformatics of bacterial genomes.
  3. Mathematical modeling/ computer simulation.

GENOMES:

  1. Discovery and analysis of genomic sequence from key protists.
  2. Comparative bioinformatics of protist genomes as grist for hypothesis-driven research in the lab.

INTRONS:

  1. Understanding of the origin and evolution of spliceosomal introns
  2. What are their roles in eukaryotic genome evolution? What is their phylogenetic distribution?

Research Modes

Not applicable

Research Paradigms

Developmental Genetics, Gene Therapy

Applications

Evolution and Phylogeny, Reproduction

Organisms

Plant
Anna Malkova Ph.D.
Associate Professor
Biology

The work in our lab is aimed on investigation of the mechanisms of double-strand break (DSB) repair. DSB is the most lethal form of DNA damage, and we would like to unravel their role in genome destabilization. In particular, we are interested in how imprecise or faulty repair of DSBs leads to structural genomic variations including mutations, copy number variations (CNVs) and chromosomal rearrangements similar to those that cause genetic diseases and cancer in humans. Our research is focused on one particular pathway of DSB repair called Break-Induced Replication (BIR). BIR is the main pathway to repair broken chromosomes containing only one repairable end, which can result from the collapse of a replication fork or from telomere erosion. Importantly, BIR plays a significant role at the onset of carcinogenesis, when cells undergo a massive collapse of replication forks, and which are repaired by BIR

Research Modes

Experimental

Research Paradigms

Mutation, Transcription and Transcriptional Regulation

Applications

Cancer

Organisms

Yeast and Fungi
John R Manak Ph.D.
Associate Professor
Biology

Research in my laboratory covers three different but not mutually exclusive areas: 1) high-throughput genomics technologies to identify the genetic basis of human disease, 2) fruit fly models to understand human diseases such as epilepsy and cancer, with an emphasis on chromatin structure, 3) genomic technology development to facilitate identification of important mutations in both humans and model organisms. 

For the first project, we are utilizing array-based comparative genomic hybridization (aCGH) to identify copy number variants associated with a number of diseases, including cleft lip and palate, spina bifida, and renal agenesis (all relatively common birth defects).  Using this approach, we identify genes whose copy number is altered in affected individuals, and we functionally validate these disease-associated genes in vertebrate animal models such as frogs and fish.  Additionally, we are using exome sequencing to explore the genetic basis of the aforementioned diseases.  This new genomics technology allows enrichment and high-throughput sequencing of the protein-coding exons in the human genome; since roughly 85% of the mutations causing Mendelian disorders are thought to reside in such exons, this strategy eliminates the need for costly whole-genome sequencing.  However, this type of analysis requires careful selection of pedigrees that show strong Mendelian inheritance patterns of the disease, which is turn suggest that high effect loci are at play in the disease process in these families. 

For the second project, we are studying the Drosophila homolog of the c-Myb proto-oncogene (which causes leukemia and lymphoma in birds and mammals).  In particular, we are exploring the role of Drosophila Myb (Dm-Myb) in modulating chromatin structure and controlling gene expression.  Our recent results demonstrate that the Myb protein is controlling gene expression through its interaction with other chromatin-modulating factors, and that Myb is regulating different targets in different cell types.  Most interestingly, in contrast to the dogma in the field, Myb is a potent repressor of large numbers of genes in certain specialized cell types.

Additionally, we are using the Drosophila system to model another human disease, myoclonic epilepsy.  We have shown for the first time that the same gene mutated in flies, mice and humans causes this form of epilepsy, and that the epileptic flies can be successfully treated with human anti-epileptic medications (Am J Hum Genet, 2011).  Intriguingly, the mutated gene is prickle, a gene that has been shown to be involved in establishing planar cell polarity.  A number of laboratories have worked on this gene over the course of many years with regard to its involvement in planar polarity; however, up until now the epileptic behavioral phenotype had been missed.        

For the third project, we are developing a novel mutation mapping technology (in collaboration with my colleague in the dept, Josep Comeron) in order to efficiently and cost-effectively map both human disease-causing mutations as well as mutations of interest in a variety of model organisms, including mice and flies.  Currently, our technology can correctly identify known SNPs with an accuracy of 99% and we are now using the technology to identify novel mutations in several human diseases.    

Research Modes

Computational, Experimental

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways, Chromatin and Histone Modifications, DNA Methylation and Epigenetics, Genetic Association Studies, Genetic Engineering, Mutation, Network and Systems Biology, Neurogenetics, Protein-protein Interactions, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Behavior and Mental Disorders, Cancer, Development and Dysmorphology, Drugs and Pharmacogenomics, Nervous System

Organisms

Drosophila, Human
Bryant F McAllister Ph.D.
Associate Professor
Biology

My research interests are in the field of evolutionary genetics, especially in processes occurring at or influenced by the genome. Active research projects in the lab are primarily concerned with using the fly species Drosophila americana to understand the factors influencing chromosomal change and the mechanisms involved in the differentiation of sex chromosomes. Changes in chromosomal arrangement are common, but their significance is unknown. We are currently examining a chromosomal rearrangement involving a centromeric fusion of the X chromosome and an autosome in D. americana. This derived arrangement exists as a polymorphism with the ancestral arrangement, showing a strong latitudinal cline in the central and eastern US. Population genetic analyses are used to examine the hypothesis that these alternative chromosomal arrangements coordinate adaptive genetic variation. Independently evolved pairs of sex chromosomes exhibit similar patterns of differentiation. The Y chromosome is genetically inert, and the X chromosome contains many active unique genes and often compensates for differences in dosage between genders. The X-4 centromeric fusion in D. americana provides a system for examining the earliest asymmetries between newly evolved sex chromosomes. We are testing models of sex chromosome evolution by examining patterns of sequence variation on this pair of neo-sex chromosomes.

Research Modes

Experimental

Research Paradigms

Mutation, Population Genetics, Sequencing and Variant Detection

Applications

Evolution and Phylogeny

Organisms

Drosophila
Paul B McCray M.D.
Professor
Pediatrics

Dr. McCray has a long-standing interest in the pathogenesis and treatment of cystic fibrosis. His laboratory has two main areas of investigation: 1) innate mucosal immunity in the lung and how this is altered in disease states, and 2) gene transfer for the treatment of inherited diseases.

Studies of the anti-microbial properties of the airway surface liquid have stimulated interest in the anti-microbial proteins and peptides secreted by epithelia. Dr. McCray's lab is currently defining the tissue specific expression, regulation and anti-microbial activity of epithelial defensins and other proteins in model systems. These molecules may play a role in the innate mucosal immunity of the lung and other mucosal surfaces. A major effort is directed towards identifying novel host defense genes using genomics and large scale expression profiling.

Another area of investigation is the development of integrating viral vectors for the treatment of inherited diseases. Current projects include gene transfer to airway epithelia for cystic fibrosis and gene transfer to the hepatocytes for the treatment of hemophilia A. The focus of these studies is on the development and optimization of retrovirus-derived vectors. A long-term goal is to develop strategies with integrating vector systems that could be successfully used to treat genetic diseases.

Research Modes

Computational, Experimental

Research Paradigms

Gene Therapy, Genetic Engineering, MiRNA and Post-transcriptional Regulation, Mutation, Network and Systems Biology, Non-coding RNA, Protein Folding and Structure, Transcription and Transcriptional Regulation

Applications

Immune System, Microbiome and Infectious Diseases, Respiratory System

Organisms

Human, Microbial and Viral, Rodent (mouse/rat), Swine
Jake Michaelson Ph.D.
Assistant Professor
Psychiatry

The Michaelson lab investigates how variation in the genome affects the development and function of the mind. Our experience in genome informatics and statistical learning enables us to develop predictive models of gene-phenotype relationships based on high-throughput biological data sets. These models serve a dual purpose: 1) they improve our diagnostic/prognostic capabilities and 2) they illuminate the biological mechanisms that underlie psychiatric conditions. We have a particular interest in conditions that manifest themselves in childhood, such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), specific language impairment (SLI), and developmental coordination disorder (DCD). These and other related conditions show striking comorbidity, and investigating their interrelationships will accelerate our understanding of their roots and potential treatments.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Chromatin and Histone Modifications, Gene-environment Interactions and Interplay, Genetic Association Studies, Machine Learning, Mutation, Network and Systems Biology, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Behavior and Mental Disorders, Development and Dysmorphology, Language, Nervous System

Organisms

Human, Rodent (mouse/rat)
Scott  Moye-Rowley Ph.D.
Professor
Molecular Physiology & Biophysics

Our laboratory has two primary research interests centered on transcriptional control of gene expression. The first involves the study of the function of a yeast transcriptional regulatory protein. This yeast protein was designated Yap1p by virtue of its homology with a mammalian proto-oncoprotein, c-Jun. c-Jun is a component of a complex DNA binding activity present in animal cells referred to as AP-1. We have constructed yeast strains in which the normal YAP1 gene has been deleted. These yap1 mutant yeast cells were found to be hypersensitive to oxidative stress agents. Additionally, it has been found that both the transcriptional activity and nuclear localization of Yap1p is stimulated by oxidative stress. We are dissecting the molecular events that lead to the activation of Yap1p function using a combination of genetics, molecular biology and biochemistry. The second area of investigation concerns the ability of particular mutant strains of yeast to simultaneously acquire resistance to several cytotoxic drugs with unrelated actions. This phenomenon, called pleiotropic drug resistance (Pdr) in yeast, is related to the multidrug resistance phenotype shown by mammalian tumor cells. Multidrug resistance is a major problem in chemotherapeutic treatment of cancer patients. Recent experiments have demonstrated that the functional status of the mitochondria is a key determinant of the level of gene expression of PDR loci. We are investigating the signaling pathway leading from the mitochondria to the nucleus that ultimately results in the induction of PDR gene expression. We will continue to use Pdr in yeast as a model for the mammalian phenotype to gain insight into the molecular events involved in eliciting multidrug resistance.

Research Modes

Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, Gene-environment Interactions and Interplay, Genetic Engineering, Mutation, Protein-protein Interactions, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Drugs and Pharmacogenomics, Microbiome and Infectious Diseases

Organisms

Yeast and Fungi
Robert F Mullins Ph.D.
Professor
Ophthalmology & Visual Sciences
  • Biology and pathology of the choroidal microvasculature in aging and macular disease
  • Mechanisms involved in the development of drusen, especially with regard to the role of humoral and cellular immune systems in drusen biogenesis
  • Structural and compositional changes in Bruch's membrane in aging and disease, and their effects on ocular physiology
  • Animal and in vitro models of age-related macular degeneration
  • Cell biology of inherited retinal diseases

Research Modes

Experimental

Research Paradigms

Genetic Association Studies

Applications

Ageing, Cardiovascular System, Eye and Vision, Stem Cells

Organisms

Human, Rodent (mouse/rat)
Jeff C Murray M.D.
Professor
Pediatrics

Advances in molecular biology, epidemiology, quantitative analysis and developmental biology have made it possible to identify genes involved in common complex traits in humans. Our laboratory applies these tools to study birth defects and prematurity. One project includes strategies to identify and characterize genes involved in cleft lip and palate, an inherited human birth defect. We have identified several genes involved in facial development and are studying their environmental covariates and clinical impact. For prematurity, a condition that causes 3 million deaths worldwide each year, we are using large sample collections and genome wide linkage and association to study thousands of individuals for millions of gene variants to generate enormous power for gene detection. Many of our studies are carried out using large population and epidemiologic studies of children , particularly from the Philippines, Japan, Denmark and Brazil, and we work in close collaboration with investigators in these countries. The studies of prematurity require clinical, biological and bioinformatic collaboration. We are also involved in studies of the prevention and better treatment of children with these disorders. Combining our molecular and developmental expertise with studies of epidemiology and environmental causes, holds out the promise for developing a better understanding of both rare disorders and common conditions. We are now developing strategies for prevention that include manipulation of genes or gene-environment interactions to prevent the primary occurrence of these tragic disorders. Graduate students serve in leadership roles for these projects and have primary responsibility for project design, implementation and publication. We are strongly committed to providing opportunities for students in the classroom, the laboratory and in fieldwork to develop their interests and expertise in the application of genetic tools to an understanding of human disease.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

DNA Methylation and Epigenetics, Gene-environment Interactions and Interplay, Genetic Association Studies, Mutation, Population Genetics, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Behavior and Mental Disorders, Development and Dysmorphology, Language, Metabolism and Nutrition, Microbiome and Infectious Diseases, Public Health and Epidemiology

Organisms

Human
Robert A Philibert M.D., Ph.D.
Professor
Psychiatry
The Psychiatric Genetics Laboratory is located on the first-floor of the Medical Education Building.  The laboratory is headed by Rob Philibert M.D. Ph.D., a Professor of Psychiatry, a member of both the Neuroscience and Genetics Program, and adjunct faculty member of the Department of Biomedical Engineering. The laboratory personnel are an eclectic mix of full-time research assistants, graduate students, database managers and work-study students.
 
The primary focus of the laboratory group is to generate a translational understanding of substance use and to increase the effectiveness of substance use interventions. We approach this task through two methods. The first is to devise more effective clinical interventions. The second is to better understand the molecular biology and generate clinically useful biomarkers. Already, our laboratory is perhaps the leading laboratory in the world for understanding the epigenetic effects of tobacco, alcohol and cannabis use on DNA methylation. These discoveries have led to the development of novel biomarkers and the founding of a diagnostic biomarker company (Behavioral Diagnostics; www.bdmethylation.com). Through iterative interactions with our clinical collaborators, we continue to better define the biology and clinical phenomena of substance use.  Our group is actively engaged in academic and commercial ventures to use this biological information to improve clinical response to substance use interventions.
 
A secondary focus the laboratory is to understand the role of genetic variation and gene-environment interactions in genesis behavioral disorders. In particular, our laboratory group has a broad portfolio in the role of VNTRs in the serotonin transporter (5HTTLPR), dopamine receptor (DRD4) and MED12 in etiology of psychiatric illness.
 
The laboratory is well-equipped to pursue these tasks. It is fully equipped for translational genetics. Major pieces of equipment include a Fluidigm Biomark genetic analysis system,an epifluorescence microscope capable of 3-D imaging, a Biomek 3000 liquid handling robot and an Applied Biosystems 7900 HT real-time machine, two cell culture hoods, and a number of state-of-the-art thermal cyclers, incubators and centrifuges. The in-house clinical resources are extremely large and include approximately 30,000 DNA samples, 3000 human cell lines and 4000 paired DNA/Sera collections from well-characterized subjects from longitudinal studies.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, DNA Methylation and Epigenetics, Gene-environment Interactions and Interplay, Network and Systems Biology, Transcription and Transcriptional Regulation

Applications

Behavior and Mental Disorders, Cancer, Immune System, Nervous System, Public Health and Epidemiology, Respiratory System

Organisms

Human
Bryan T Phillips Ph.D.
Assistant Professor
Biology

How does an egg become an adult?
The means by which a single undifferentiated oocyte develops into a multicellular organism with numerous, intricately connected cell types is a major focus in developmental biology. Defects in the process of cell fate determination can lead to disease or death. Cell-to-cell communication is a common way that a cell (or a group of cells) is instructed to proceed down one particular developmental path versus another. One way that cells execute these instructions is through asymmetric division of a polarized mother cell, generating two daughter cells that contain different fate determinants and thus proceed down different developmental paths.

C.elegans as a model for developmental genetics
Since all multicellular animals progress through development by overcoming similar developmental obstacles, the molecular mechanisms that overcome these obstacles have often been conserved during evolution. We use the nematode, Caenorhabditis elegans, to address the problem of how cell differentiation works in multicellular animals. C. elegans has many attributes that make it well-suited to study developmental biology, including excellent genetics, transgenics, and a sequenced genome. Especially important for our research, C. elegans also uses conserved cell signaling pathways to polarize mother cells and induce asymmetric divisions throughout its development.

The importance of communication
The Wnt signaling pathway regulates cell fate in many animals, including nematodes and mammals. Wnt signaling stabilizes a transcriptional coactivator called β-catenin, which then binds to TCF/LEF DNA-binding proteins and converts them into activators of Wnt target gene expression. β-catenin regulation is therefore a crucial step in the Wnt signaling pathway. β-catenin mis-regulation is associated with developmental defects and human diseases such as cancer. Wnt signaling also regulates many asymmetric divisions in C. elegans. An essential component of this pathway in C. elegans is SYS-1, which binds TCF transcription factors and upregulates transcription of Wnt target genes much as β-catenin does in other organisms. The crystal structure of SYS-1 confirms that SYS-1 has the structural hallmarks of the β-catenin family of transcriptional coactivators.  SYS-1 shows a remarkable conservation of structure and function when compared to vertebrate β-catenin. We use these similarities (and the differences between the β-catenins) to dissect how β-catenins work. Other areas of interest in the Phillips lab are determining how the Wnt pathway functions in C. elegans, SYS-1/β-catenin regulation, and β-catenin evolution. These studies will help us understand the larger question of why animal cells differentiate the way they do.

Research Modes

Experimental

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways, Developmental Genetics, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Cancer, Development and Dysmorphology

Organisms

C. Elegans
Robert C Piper Ph.D.
Professor
Molecular Physiology & Biophysics

Our laboratory is interested in how proteins are degraded in lysosomes. This is a fundamental process of all eukaryotic cells necessary for regulating a variety of cell surface proteins. This process is often termed “downregulation”, and is a central feature of virtually all physiological processes that rely on cell surface membrane proteins. Failure to properly downregulate particular proteins can lead to or exacerbate a variety of pathophysiological conditions such as cancer, hypertension, and cardiac disease.. Our overall goal is to understand the protein machinery common in all cell types that controls the delivery of membrane proteins to the lysosome. There are two processes that we examine: the first is how proteins are designated and recognized for delivery to the lysosome. The second is how transport through the endocytic pathway via endosome membrane fusion events is controlled.

Our primary focus is one finding out how individual “cargo” proteins are selected and designated for transport and degradation in the lysosome. Membrane proteins can initiate their journey to lysosomes from a number of cellular compartments. At the cell surface, proteins can enter the endocytic pathway via internalization. At the Golgi apparatus, proteins can be sorted into transport vesicles that are targeted to endosomes. Perhaps the most critical sorting step controlling the degradation of membrane proteins in lysosomes, is the incorporation of protein cargo into vesicles that bud into the lumen of the endosome. This sorting step occurs within endosomes and leads to the formation of multivesiculated bodies (MVBs) that accumulate lumenal membranes. These lumenal membranes are then subject to degradation by lysosomal lipases and proteases, thereby ensuring the complete destruction of integral membrane proteins.. A variety of studies in both yeast and mammalian cells have established that this sorting step is conferred by the post-translational attachment of ubiquitin, a 76 amino acid peptide that is covalently linked to lysine residues via an isopeptide bond.. Currently we are determining how ubiquitinated cargo is recognized and incorporated into transport vesicles destined for the lysosome.

Research Modes

Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Protein Folding and Structure, Protein-protein Interactions, Translation and Post-translational Modifications

Applications

Cell Biology

Organisms

Yeast and Fungi
James B. Potash M.P.H., M.D.
Paul W. Penningroth Chair, Professor and Head of Psychiatry

I am interested in the genetic variation and DNA methylation variation that confer susceptibility to depression and bipolar disorder. Family, twin, and adoption studies have made it abundantly clear that thesedisorders are substantially heritable, but only a very small proportion of that heritability has thus far been explained molecularly. Similarly, the environment clearly plays a role in the etiology of depression, but the molecular basis of that role remains undefined. I have an R01 grant from the NIMH to perform next-generation exome sequencing in about 3,000 bipolar disorder cases and controls, and examine the data searching for rare variants associated with this illness. I also have an R01grant from the NIMH to assess genome-wide DNA methylation variation in a mouse model of stress and depression. Both of these projects involve bench work including DNA sequencing, bisulfite pyrosequencing, and gene expression assays. They further involve bioinformatics and statistical genetics assessment of large data sets.

Research Modes

Computational, Experimental

Research Paradigms

DNA Methylation and Epigenetics, Genetic Association Studies, Sequencing and Variant Detection

Applications

Behavior and Mental Disorders

Organisms

Human, Rodent (mouse/rat)
Matthew J Potthoff Ph.D.
Assistant Professor
Pharmacology

The regulation of metabolic homeostasis is a complex process coordinated by numerous growth factors and hormones signaling the availability of energy and nutrients. Organisms must properly perceive and respond to these signals to maintain homeostasis. The main goals of my lab are: 1) to identify secreted proteins and transcription factors that regulate nutritional status and contribute to metabolic disease, 2) to determine molecular mechanisms for these signals, 3) to understand how these pathways regulate biological functions, and 4) how dysregulation of these pathways contribute to metabolic disease (i.e., in diabetes and cancer). To accomplish these goals, my lab integrates biochemistry, proteomics, cell biology, metabolomics, and mouse genetics. We currently have multiple projects aimed at addressing these goals, with the two main projects focused on the endocrine fibroblast growth hormone 21 (FGF21) and a hepatic transcription factor termed Tox.

In mammals, the liver is important in maintaining whole body energy balance during feeding and fasting through regulation of carbohydrate and lipid metabolism. While hormones such as insulin and glucagon have long been known to control energy balance in response to nutritional status, additional metabolic hormones, including FGF21, have recently been shown to be important regulators of hepatic metabolism. FGF21 is an atypical FGF that lacks the conventional heparin-binding domain found in most other members of the FGF family. As a consequence, endocrine FGFs can circulate as hormones and signal through cell-surface receptors comprised of classical FGF receptors (FGFRs) complexed with beta-Klotho. Our previous work has demonstrated that FGF21 is sufficient to drive the hepatic fasting response by rapidly inducing hepatic expression of peroxisome proliferator-activated receptor gamma coactivator protein-1alpha (PGC-1alpha), a key transcriptional regulator of energy homeostasis (Potthoff et al. 2009). More recently, FGF21 was shown to act on white and brown adipose tissue, and these actions of FGF21 likely represent an extension of its role in the adaptive starvation response. In contrast to the physiological actions of FGF21 in lean animals, pharmacological studies have shown that FGF21 administration markedly improves insulin sensitivity, lowers lipid levels, and reduces body weight in obese animal models. Thus, FGF21 remarkably improves a number of metabolic parameters in obese rodents. The mechanism by which endocrine FGFs perform these remarkable pharmacologic effects on carbohydrate and lipid metabolism is largely unknown and is currently an area of interest of the lab.

A second line of investigation in the lab is how Tox, a transcription factor, regulates hepatic lipid and glucose metabolism in vivo. Using genetically engineered Tox total and liver-specific conditional KO mice, as well as mice with acute liver-specific overexpression of Tox via adenovirus injection, we will elucidate the function of Tox during fasting and obesity. Our recent findings suggest that Tox is an important regulator of hepatic lipid and glucose metabolism during both of these conditions. The precise mechanism of Tox action is unclear, but we are currently using multiple techniques to identify Tox target genes in the liver and the mechanism by which it regulates carbohydrate and lipid metabolism in vivo. By identifying and studying pathways which signal energy and nutrient availability, we hope to gain insight into metabolic dysfunction and find novel candidates for the treatment of metabolic disease.

Research Modes

Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Transcription and Transcriptional Regulation

Applications

Cancer, Metabolism and Nutrition

Organisms

Rodent (mouse/rat)
Veena Prahlad Ph.D.
Assistant Professor
Biology

Cellular protein misfolding leads to the occurrence of amyloid oligomers and protein aggregates inside the cell.  Protein misfolding is the cause of cellular dysfunction associated with numerous diseases such as cardiomyopthy, Huntington’s disease, Alzheimer’s disease, adult onset diabetes, cancer and others.  To protect themselves against toxic stressors and concomitant protein aggregation, all cells possess highly conserved surveillance and repair mechanisms. One of the most central of these is the stress responsive transcriptional program called the ‘heat shock response’, controlled by the heat shock transcription factor 1 (HSF1). HSF1 upregulates a set of cytoprotective proteins, the so-called heat shock proteins (HSPs) which help refold and/or degrade damaged proteins to restore homeostasis.  Previously, we have shown that in the animal model Caenorhabditis elegans the upregulation of HSPs upon protein misfolding is not regulated cell autonomously by the amounts of protein misfolding, but instead, is under the control of the organism’s nervous system.  Our lab works on understanding how the nervous system of C. elegans controls the cellular response to stress and protein misfolding. Specifically, we use the powerful genetic techniques afforded to us by the use of C. elegans to ask:

a)  What genes and signaling pathways are involved in how the nervous system detects suboptimal environmental conditions, or stress
b)  What signaling pathways are responsible for transmitting this information to non-neuronal cells
c)  How is the accumulation of protein damage in non-neuronal cells communicated to the nervous system
d)  How do these signaling mechanisms ultimately result in an adaptive, organimal response to macromolecular damage and stress.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Imaging, Mutation, Protein Folding and Structure, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Ageing, Endocrine System, Immune System, Nervous System, Stem Cells

Organisms

C. Elegans
Andy F Russo Ph.D.
Professor
Molecular Physiology & Biophysics

My research interest is the control of neuronal gene expression. The major focus of the lab is on the neuropeptide CGRP and its role in migraine. The role of CGRP in migraine is supported by the ability of CGRP to cause headache and the recent efficacy of a CGRP antagonist as an antimigraine drug. We have found that the CGRP gene is up-regulated by cytokine-induced MAP kinases and repressed by antimigraine drugs that appear to act via an unusually prolonged calcium signal. We are currently investigating these mechanisms using adenoviral-mediated gene transfer to cultured trigeminal neurons and intact ganglia in vivo. We are also using gene transfer and transgenic mice to regulate CGRP receptor activity in the vasculature and nervous system by overexpressing the RAMP1 subunit of the CGRP receptor. The RAMP1 transgenic mice are sensitized to CGRP-induced neurogenic inflammation. The RAMP1 transgenic mice display a unique phenotype has raised the possibility that these mice may provide a model for some aspects of migraine, which is currently being explored. In collaborative projects, we are studying the beneficial effects of CGRP against hypertension and following myocardial infarction in the RAMP1 mice. Other collaborative projects include the regulation of serotonin biosynthesis, which may be important in migraine and behavioral disorders, and use of the CGRP promoter to target a dominant negative oncogene to specific neuroendocrine cells. The overall goal of these projects is to develop effective diagnostic and therapeutic strategies.

Research Modes

Clinical, Experimental

Research Paradigms

Cellular Signalling Pathways, DNA Methylation and Epigenetics, Genetic Engineering, Transcription and Transcriptional Regulation

Applications

Cardiovascular System, Eye and Vision, Nervous System, Stem Cells

Organisms

Rodent (mouse/rat)
Todd E Scheetz Ph.D.
Professor
Ophthalmology and Visual Sciences

Dr. Scheetz's research interests focus on bioinformatics, genomics, systems biology, and genetic analyses including genotype-phenotype correlation and genome-wide association studies. Much of his research is performed in collaboration with other faculty within the University of Iowa and other institutions. These collaborative projects include analysis of genomic integration patterns, analysis of expression, and identification of regulatory elements in the mammalian eye.

Research Modes

Computational

Research Paradigms

Genetic Association Studies, Imaging, Network and Systems Biology, Sequencing and Variant Detection, Splicing, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology, Eye and Vision, Nervous System

Organisms

Human, Rodent (mouse/rat), Zebrafish
Alberto M Segre Ph.D.
Professor and Chair
Computer Science

The focus of my research is on nagging, a distributed search paradigm that exploits the speedup anomaly by playing multiple reformulations of the problem—or portions of the problem—against each other. Originally developed within the relatively narrow context of distributed automated deduction, we have recently shown how nagging can be generalized and used to parallelize three other standard search algorithms (i.e., A* search, alpha-beta-minimax game tree search, and the Davis-Putnam search algorithm from the artificial intelligence literature. Our results clearly show, both empirically and analytically, the performance advantage of nagging over partitioning for some search algorithms and problem domains. Aside from performance considerations, we note that nagging holds several additional practical advantages over partitioning; it is intrinsically fault tolerant, naturally load-balancing, requires relatively brief and infrequent interprocessor communication, and is robust in the presence of reasonably large message latencies. These properties contribute directly to nagging's demonstrated scalability, making it particularly well suited for use on geographically-distributed networks of processing elements. More recently, I have begun to work on applications of nagging to two important biological optimization problems, both of which have become the topic of ongoing multidisciplinary collaborations between our laboratory and other University of Iowa faculty in the life sciences. The first involves finding the 'best' three-dimensional conformation of a protein (or portion of a protein) with respect to some model of protein energetics, while The second involves using patterns of heritability to find the 'most likely' location of the DNA mutation responsible for a disease. All of these projects are based on the NICE infrastructure, which is actively under development in our laboratory. My research is supported by the National Science Foundation.

Research Modes

Computational

Research Paradigms

Medical Informatics

Applications

Public Health and Epidemiology

Organisms

Human
Val C Sheffield M.D., Ph.D.
Professor
Pediatrics

My laboratory is interested in identifying and understanding the function of genes which cause a variety of human disorders. Our research efforts have focused on the molecular genetics of monogenic disorders, as well as polygenic and multifactorial disorders. Our research efforts have resulted in the mapping of many different disease loci. In addition, we have used positional cloning methods to identify genes involved in a number of different diseases including hereditary blindness and deafness. Efforts are currently underway to use positional cloning strategies to identify additional disease-causing genes. Complex genetic disorders currently under investigation in the laboratory include hypertension, obesity, congenital heart disease and autism. In addition, we have worked on developing and improving techniques for disease mapping, positional cloning, and mutation detection. We have also had an active role in the human genome project and the rat genome project.

Research Modes

Clinical, Experimental

Research Paradigms

Cellular Signalling Pathways, Mutation, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Development and Dysmorphology, Eye and Vision

Organisms

Human, Rodent (mouse/rat)
Curt D Sigmund Ph.D.
Professor
Pharmacology

Peroxisome proliferator activated receptors (PPAR's) are ligand activated transcription factors which have a pleiotropic role in many physiological processes. PPARγ is the molecular target of the thiazolidinediones class of drugs which are used to treat patients with non-insulin dependent diabetes mellitus (NIDDM). Endothelial dysfunction, which develops in patients that are diabetic or chronically hypertensive, is thought to contribute to the progression of carotid artery disease, cerebral vascular dysfunction and stroke. PPARγ is expressed in vascular endothelium and smooth muscle and therefore is a potentially important factor in the regulation of vascular function and blood pressure. PPARγ has been reported to inhibit responses to vasoconstrictors such as endothelin, stimulate the release of vasodilators, and increase expression of CuZn-SOD in vascular muscle and endothelium. Importantly, patients carrying dominant negative mutations in PPARγ exhibit early onset type II diabetes and hypertension. Current data suggests that PPARγ exerts a protective effect in the vessel wall and we hypothesize that PPARγ plays an important role in the regulation of vascular function and blood pressure. We are currently testing this hypothesis using a variety of genetic, computational and Bioinformatic tools. We are: 1) using adenoviruses over-expressing wildtype and dominant negative mutations of PPARγ in blood vessels from normotensive and hypertensive mice to test whether they can alter endothelial function, 2) developing novel transgenic mice with expression of the wild-type and dominant negative mutants of PPARγ targeted specifically to vascular muscle and endothelial cells using cell-specific promoters, 3) using microarrays to determine the transcriptional targets of PPARγ, and 4) using computational and Bioinformatic tools to scan genomic sequences for PPARγ response elements (PPRE).

Research Modes

Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Mutation, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Cardiovascular System, Nervous System

Organisms

Rodent (mouse/rat)
Diane C Slusarski Ph.D.
Professor
Biology

Our research focuses on cell-cell signaling events that lead to intracellular calcium release. We integrate in vivo image analysis coupled with molecular-genetic tools to elucidate the role of calcium-dependent signaling networks critical in developmental processes such as body plan formation and organogenesis in the zebrafish. The zebrafish model system for vertebrate developmental biology has many attributes including genetics, rapid development and translucent embryos. We defined a class of Wnt signaling ligands that modulate intracellular calcium release and are investigating the mechanisms by which this Wnt/calcium class mediates its biological effect on the developing embryo. As inappropriate Wnt signaling has been associated with a high frequency of tumors, we are also investigating spontaneous tumor formation in genetic backgrounds that disrupt the function of Wnt/calcium class ligands. Additionally, we have determined that the calcium release requires G-protein signaling. To identify potential intracellular regulators of calcium release dynamics, we are characterizing members of the regulators of G-protein signaling protein family. We have cloned and characterized a few members of the RGS family and find they have essential roles in sensory neuron and somite patterning. Due to the remarkable conservation of developmental processes and mechanisms among vertebrates, we also use zebrafish as a model for human disease and test candidate genes. Of note are studies involving retinal degeneration and Bardet-Biedl Syndrome.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Splicing, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Cancer, Cardiovascular System, Development and Dysmorphology, Eye and Vision

Organisms

Zebrafish
Richard J Smith M.D.
Professor and Vice Chair
Otolaryngology

My laboratory is studying the genetic basis of deafness and membranoproliferative glomerulonephritis type 2 (MPGN 2). Hereditary deafness is common. It affects 1:2,000 newborns and accounts for greater than 50% of severe-to-profound childhood deafness. It also affects the elderly. Nearly 50% of octogenarians have difficulty communicating without the use of amplification, and in many, the cause is genetic. Inherited hearing impairment can occur with other co-inherited clinical features to form a recognized phenotype (syndromic hearing loss) or appear in isolation (non-syndromic hearing loss). Non-syndromic hearing loss accounts for approximately 70% of genetic deafness. It is almost exclusively monogenic and is highly heterogeneous, with some estimates of the number of deafness-causing genes exceeding 100. We are studying both syndromic and non-syndromic types of deafness. Projects include gene localization by linkage analysis and homozygosity mapping, mutation screening and detection, a variety of functional studies, and hearing-related research on mouse mutants targeting specific genes by RNAi. Membranoproliferative glomerulonephritis type 2 is also called Dense Deposit Disease (MPGN II/DDD). It causes chronic renal dysfunction that leads to kidney failure and a retinal disease similar to age-related macular degeneration, which is the most common cause of blindness in the elderly. Deficiency of and mutations in complement Factor H (CFH) are associated with development of MPGN II/DDD. Changes in CFH are also associated with another renal disease, atypical hemolytic uremic syndrome, and with age-related macular degeneration. We are studying relationships between the alternative pathway of the complement cascade, the structure of the glomerular basement membrane, and MPGN II/DDD to better understanding the pathophysiology of this disease.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, Genetic Association Studies, Genetic Engineering, Imaging, MiRNA and Post-transcriptional Regulation, Mutation, Network and Systems Biology, Population Genetics, Protein Folding and Structure, Protein-protein Interactions, Sequencing and Variant Detection, Splicing, Transcription and Transcriptional Regulation, Translation and Post-translational Modifications

Applications

Drugs and Pharmacogenomics, Hearing, Immune System

Organisms

Human, Rodent (mouse/rat), Zebrafish
Sarit  Smolikove Ph.D.
Associate Professor
Biology

Our research focuses on the evolutionarily conserved process of meiosis, using C. elegans as a model system. Meiosis enables sexual reproduction by the production of haploid gametes. A successful meiotic division relies on the formation of crossover events between each pair of homologous chromosomes. These crossover events are formed in the context of the synaptonemal complex (SC), a protein complex that bridges paired homologous chromosomes during meiotic prophase I.  Hence, in the absence of a functional SC, meiosis is abrogated. Perturbation of meiosis can lead to chromosome nondisjunction, which is the leading cause for miscarriages and birth defects in humans. These observations, combined with evidence from studies of infertile patients, suggest a connection between SC dysfunction and chromosomal nondisjunction in human reproduction. In our lab we aim to discover and characterize novel genes essential for various aspects of meiosis, including genes essential for chromosome pairing, recombination, and the regulation of SC assembly and disassembly. To accomplish this goal, we are engaged in genetic screens targeted to isolate genes in these processes. This approach has already resulted in the identification of a novel class of mutants affecting SC disassembly. We combine our genetic approaches with high-resolution microscopy to investigate the role of these proteins in meiosis. These studies will result in a better understanding of the various fundamental processes unfolding in C. elegans meiosis and will lead to insights into this basic process in other organisms as well. In-depth investigation of meiosis is of central importance for progress in developing methods to prevent and treat infertility and birth defects stemming from meiotic chromosome nondisjunction in humans.

Research Modes

Experimental

Research Paradigms

Cell Cycle/replication/recombination, Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Sequencing and Variant Detection, Translation and Post-translational Modifications

Applications

Cancer, Reproduction

Organisms

C. Elegans
Edwin M Stone M.D., Ph.D.
Professor
Ophthalmology

Our laboratory studies inherited eye diseases. Projects range from attempts to map disease-causing genes with linkage analysis and positional approaches to the molecular characterization of specific mutations once the disease-causing genes have been identified. Diseases actively under study include: age related macular degeneration; glaucoma; retinitis pigmentosa; hereditary myopia; corneal dystrophies; Leber's hereditary optic neuropathy. Students and fellows in the laboratory are encouraged to participate in the clinical examination of patients as well as in the molecular investigation of the diseases.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Gene-environment Interactions and Interplay, Genetic Association Studies, Genetic Engineering, Imaging, Mutation, Population Genetics, Sequencing and Variant Detection, Splicing, Transcription and Transcriptional Regulation

Applications

Eye and Vision, Immune System, Stem Cells

Organisms

Human, Rodent (mouse/rat), Swine
Tina  Tootle Ph.D.
Assistant Professor
Anatomy and Cell Biology

Prostaglandins are transiently acting hormones that are synthesized at their sites of action by cyclooxygenase (COX) enzymes, the targets of Aspirin and Advil, to mediate a variety of biological activities, including inflammation, sleep, reproduction, and cancer development. How do prostaglandins regulate these diverse, cellular events? To address this question we have developed Drosophila oogenesis as a new a new and powerful model for studying prostaglandin signaling. Using both pharmacology and genetics, we discovered that prostaglandins mediate Drosophila follicle development, identified the Drosophila COX1 enzyme, Pxt, and revealed that genetic perturbation of prostaglandin signaling can be used to exam the function of prostaglandins. This research on prostaglandin signaling implicates it in modulating actin/membrane dynamics, cell migration, stem cell activity, and the timing of gene expression during Drosophila follicle development. The lab is currently pursuing how prostaglandin signaling regulates actin dynamics and invasive cell migrations during Drosophila follicle development. By using a multifaceted experimental approach that combines Drosophila genetics, cell biology, live imaging, and biochemistry to we can begin to work out the mechanisms by which prostaglandins regulate these processes, and provide general insight into how prostaglandins regulate the cytoskeleton and migration at a cellular level. Such mechanisms of prostaglandin action are likely to be reutilized throughout development, including mediating the changes that occur during cancer progression and metastasis.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Translation and Post-translational Modifications

Applications

Cancer, Development and Dysmorphology, Drugs and Pharmacogenomics

Organisms

Drosophila
Lori  Wallrath Ph.D.
Professor
Biochemistry

In the nucleus, genomic DNA is packaged into nucleosomes, the fundamental packaging unit. Nucleosomal DNA is further condensed into higher order chromatin structures that are not well understood. Presently, our research is centered on Heterochromatin protein 1, HP1, that plays a central role in the formation of higher order chromatin structure and gene expression. One project is focused on mechanisms of gene silencing by HP1 using the fruit fly as a model system. We are determining the effects of tethering HP1 upstream of reporter genes that can be analyzed for changes in chromatin structure and gene expression. We are also examining the role of HP1 in metastasis using human breast cancer cells as a model system. This project grew out of a collaboration with Dr. Dawn Kirschmann of the laboratory of Dr. Mary Hendrix (Northwestern University). HP1 is significantly down regulated in highly/invasive metastatic breast cancer cells, compared with poorly invasive/non-metastatic breast cancer cells. Experiments are underway to identify genes regulated by HP1 through microarray and chromatin immunoprecipitation analyses. These data will shed light on the role of HP1 as a potential metastatsis suppressor. Last, we have iundertaken a project to determine the role of nuclear envelope associated proteins in genome organization and gene expression. This project is in collaboration with the laboratory of Pamela Geyer (Biochemistry, University of Iowa). We are currently focusing on the role of lamins, intermediate filmament proteins, that line the inner nuclear envelope, providing structural support for the nucleus and making contacts with chromatin. In humans, mutation in lamins causes a number of diseases such as Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria (early onset aging) that are collectively known as laminopathies. We are using Drosophila as a model to determine the function of A-type lamins in gene expression and development. Our studies will provide insights on the molecular defects associated with laminopathies in humans.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Chromatin and Histone Modifications, DNA Methylation and Epigenetics, Genetic Engineering, Mutation, Protein Folding and Structure, Protein-protein Interactions, Transcription and Transcriptional Regulation

Applications

Ageing, Cancer, Cardiovascular System, Metabolism and Nutrition

Organisms

Drosophila, Human
Thomas H Wassink M.D.
Professor
Psychiatry

My laboratory's goal is to identify genes that underlie susceptibility to a variety of psychiatric disorders, with our primary focus being autism. We use a variety of approaches in this endeavor, including positional cloning, sophisticated cytogenetic analyses, and candidate disease gene screening. We perform these studies in DNA obtained from numerous independent samples of families with multiple autistic individuals. We are also equipped to assess the function and expression of identified disease genes using an array of molecular and animal model techniques. Extensive additional resources and expertise are available to us here at Iowa through our collaborations with the Center for Statistical Genetics, the UIHC Cytogenetics laboratory, and the Center for Bioinformatics and Computational Biology. We are also actively investigating the genetics of panic disorder and schizophrenia. The panic disorder work uses traditional positional cloning methods and a sample of moderate to large panic disorder pedigrees. The schizophrenia genetics research is performed in association with the Department of Psychiatry's Mental Health Clinical Research Center. We collect DNA from individuals with schizophrenia, their families, and psychiatrically normal control subjects. All of these individuals participate in protocols that gather data from a wide variety of research domains, including functional and structural brain imaging, cognitive testing, disease phenomenology, longitudinal progression of disease, etc. The goal with the schizophrenia sample, therefore, is to investigate relationships between genetic information and these other types of data.

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Genetic Association Studies, Imaging, Mutation, Sequencing and Variant Detection

Applications

Behavior and Mental Disorders, Development and Dysmorphology, Nervous System

Organisms

Human
Joshua A. Weiner Ph.D.
Associate Professor
Biology

A defining characteristic of the vertebrate nervous system is the specificity with which its diverse cell types interact, especially at specialized sites of adhesive contact called synapses. It is the exquisite specificity of neuronal circuitry that underlies the brain’s unique ability to store and process information. Conversely, disruptions in the formation of this circuitry appear to precipitate such genetic developmental disorders as autism and mental retardation. Thus, elucidating the genetic basis of the specificity of neuronal interactions, the primary long-term goal of my laboratory, will greatly advance our basic scientific understanding of the most intricate system in all of biology, while providing a platform on which future therapeutic interventions might be based. My laboratory has taken a candidate gene approach, focusing on cell adhesion molecules, particularly the γ -Protocadherin (γ -Pcdh) family of cadherin-like proteins and the immunoglobulin superfamily (IgSF) member ALCAM.

Protocadherin Gene Clusters

Three large clusters of cadherin-related genes (Protocadherin-α, -β, and -γ) lie in a tandem array on a single chromosome in mammals. The γ cluster, on which we focus, consists of 22 "variable" exons, each of which encodes the extracellular, transmembrane, and partial cytoplasmic domains of a single protocadherin isoform. Each variable exon is spliced to a set of three "constant" exons which encode a shared C-terminal domain. Thus, a variety of adhesive specificities may link into a common signaling pathway.

Our work has shown that γ-protocadherins are expressed in the nervous system during development, and are found at a subset of synapses. Mice in which the entire γ-protocadherin locus is deleted lack voluntary movements and reflexes and die at birth due to massive apoptosis of spinal interneurons and concomitant loss of synapses. We have genetically dissociated these two phenotypes, using mice in which apoptosis is blocked, to show that control of synapse development is a primary function of γ-protocadherins. Our work indicates that when mice lack the γ-protocadherins, synaptic density and activity is reduced, and this leads to an exacerbation of an underlying pattern of developmental cell death amongst molecularly distinct spinal interneuron populations.

We are addressing a wide range of ongoing, critical questions:

1) Do the γ-protocadherins act exclusively or primarily as homophilic adhesion molecules, or do they engage in heterophilic interactions and/or act as signaling molecules??We recently showed that the γ-protocadherins promiscuously form cis-tetramers that then interact in a strictly homophilic manner in trans.

2) What roles to the γ-protocadherins play in  in the cerebral cortex, which matures only after birth, when the constitutive mutants die??Our ongoing work has found that the γ-protocadherins regulate dendritic arborization by inhibiting a FAK/PKC kinase cascade.

3) What is the function of the γ-protocadherins in astrocytes, glial cells that express multiple members of the family? We have shown that the γ-protocadherins are neuronal-glial adhesion molecules and that astrocytic contacts stabilize nascent synapses during development.

4) Does the diversity of the γ-protocadherin family provide a molecular code that underlies the specificity of synaptic interactions?

To answer these questions, we are utilizing new conditional mutant mice and several transgenic lines expressing the Cre recombinase to disrupt γ-protocadherin function in specific cell types at discrete developmental stages. We are also employing a variety of biochemical techniques to characterize the molecular interactions of the γ-protocadherins in neurons and in other cell types.

We hope to use insights gained from studying the functions of the γ-protocadherins to improve our general understanding of the ways in which synapse formation and function might go awry in a number of developmental disorders such as autism and mental retardation.

ALCAM

The immunoglobulin superfamily molecule ALCAM is expressed by subsets of neurons and has been implicated in the control of numerous developmental and pathological processes. To test hypotheses about ALCAM function, we have disrupted its gene via homologous recombination. In mice lacking ALCAM, both motor neuron and retinal ganglion cell axons fasciculate poorly and are occasionally misdirected. In addition, ALCAM mutant retinae exhibit dysplasias with photoreceptor ectopias that resemble the retinal folds observed in some human retinopathies (Figure 3). This appears to be due to loss of ALCAM in the choroid, a pigmented vascular tissue that lies behind the neural retina. Because ALCAM has been associated with melanoma metastasis, we hypothesize that defects in choroidal melanocyte adhesion and/or motility underlie the mutant phenotypes. We now are determining the specific cellular defect and examining its relationship to ocular development and disease processes. We are also searching for ALCAM's heterophilic binding partners and intracellular signaling pathways.

With collaborators at the University of North Carolina, we have recently characterized a role for ALCAM in the targeting of retinal axons to their termination zones in two brain targets, the superior colliculus and the lateral geniculate nucleus. ALCAM knockout mice exhibit defects in both of these retinal projections, due to disrupted trans-interaction with another member of the immunoglobulin superfamily, L1. (see Fig. 5)

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Genetic Engineering, Imaging, Protein-protein Interactions

Applications

Behavior and Mental Disorders, Cancer, Development and Dysmorphology, Immune System, Nervous System

Organisms

Rodent (mouse/rat)
David S Weiss Ph.D.
Associate Professor
Microbiology

The cell cycle culminates with the formation of a septum that divides a mother cell into two daughter cells. How the division septum is formed, and how its formation is regulated, are not well understood in any organism. Our long-term goal is to understand these processes in a relatively simple model system, the bacterium Escherichia coli. Most of the proteins required for division in E. coli also occur in pathogenic bacteria, so these proteins are attractive targets for new antibiotics. We have used gene fusion technology and fluorescence microscopy to show that several of the division proteins (FtsI, FtsL, FtsQ, and FtsW) undergo timed localization to the division site--the proteins are dispersed in newborn cells, but localize to the division site just prior to the onset of septation and remain there until division is complete. We hypothesize that these proteins are part of a large complex that assembles at the division site. Currently we are using genetic techniques, fluorescence microscopy, and biochemical assays to identify localization signals, probe for protein-protein interactions, and determine how the production and activity of these proteins is regulated during the division cycle.

Research Modes

Experimental

Research Paradigms

Cell Cycle/replication/recombination, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Transcription and Transcriptional Regulation

Applications

Microbiome and Infectious Diseases

Organisms

Microbial and Viral
Michael J Welsh M.D.
Professor
Internal Medicine; Molecular Physiology; Biophysics

The major neuroscience effort of the laboratory focuses on the biology of DEG/ENaC channels. These are a novel class of non-voltage gated cation channels, including ASIC1, -2, and -3 in mammals and the Pickpocket genes in Drosophila. The laboratory is interested in the function of these channels in the peripheral nervous system where they may serve as sensory receptors, including sensors for touch, temperature, salt taste, moisture, and pain. We are examining the function, cell biology, physiology and behavioral role of these channels in vitro and in genetically altered flies and mice. We also study the function of these channels in the central nervous system where they play an important role in synaptic plasticity, learning and memory. They may also make an important contribution to fear, including panic disorders. The lab offers the opportunity to take a variety of approaches to this field, and it provides the opportunity to work with investigators with diverse expertise. This research should lead to a better understanding of neuronal sensory systems and novel targets for therapeutic intervention. The other major focus of the lab is to understand the biology of cystic fibrosis, a common lethal genetic disease. We are investigating the function of the CFTR chloride channel, the pathogenesis of the disease, and the development of gene therapy..

Research Modes

Clinical, Computational, Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Genetic Association Studies, Genetic Engineering, Protein Folding and Structure, Sequencing and Variant Detection

Applications

Drugs and Pharmacogenomics, Nervous System, Respiratory System

Organisms

Human, Rodent (mouse/rat), Swine
Virginia L. Willour Ph.D.
Associate Professor
Psychiatry

Identifying genetic and epigenetic risk factors for suicidal behavior

The primary goal of our laboratory is to identify genetic and epigenetic risk factors for suicidal behavior.  Family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders.  In an effort to better understand the biological basis of this behavior, we have conducted a genome-wide association study (GWAS) using attempted suicide as the phenotype, an effort that identified a promising association signal on 2p25 as well as candidate genes implicating the Wnt signaling pathway and excitatory neurotransmission.  These findings have prompted us to launch a large-scale whole exome sequencing project, with the goal of identifying functional variants associated with suicidal behavior on 2p25 and throughout the genome.  Environmental stressors, such as child abuse and early parental loss, are also known to play important roles in triggering suicidal behavior, likely through interaction with genetic vulnerability factors.  With this in mind, we have begun an epigenetics project that involves assessing genome-wide methylation patterns in post-mortem brains of suicide completers and controls, with the goal of identifying differentially methylated candidate genes and regions associated with suicidal behavior.

Research Modes

Computational, Experimental

Research Paradigms

DNA Methylation and Epigenetics, Genetic Association Studies, Sequencing and Variant Detection

Applications

Behavior and Mental Disorders

Organisms

Human
Mary E Wilson M.D.
Professor
Internal Medicine and Microbiology

The protozoan parasite, Leishmania chagasi, causes the fatal human disease visceral leishmaniasis. L. chagasi express an abundant surface protease GP63, which is important for parasite survival. GP63 is encoded by >18 tandem MSP genes, falling into 3 homologous classes whose expression varies throughout the parasite life cycle. MSPL genes are expressed in logarithmic, whereas MSPS genes are expressed in stationary phase when parasites achieve maximal virulence and express high levels of GP63 protein. Our studies focus on the post-transcriptional mechanisms regulating expression of different MSP gene classes. These include mRNA T½, the efficiency of trans-splicing, and protein T½. Using reporter gene constructs and transfection techniques we are localizing unique sequences in MSP 3'UTRs that interact with regulatory proteins. Additionally, using MALDI-TOF mass spec we are examining products of specific MSP class genes that are expressed in different parasite stages.
An ongoing epidemic of visceral leishmaniasis in northeast Brazil has led to our studies genetic loci associated with different outcomes of human L. chagasi infection (asymptomatic versus fatal). Using molecular genotyping methods (microsatellites, SSCP, RFLP, sequencing) we are examining polymorphic alleles of candidate genes for their contributions to disease susceptibility, in collaboration with Dr. Selma Jeronimo of Natal, Brazil. These studies will extend to a genome-wide scan and fine mapping of loci linked to different disease outcomes.

Research Modes

Computational, Experimental

Research Paradigms

Gene-environment Interactions and Interplay, Genetic Association Studies, Genetic Engineering, MiRNA and Post-transcriptional Regulation, Non-coding RNA, Sequencing and Variant Detection, Transcription and Transcriptional Regulation

Applications

Immune System, Microbiome and Infectious Diseases

Organisms

Human, Microbial and Viral, Rodent (mouse/rat)
Chun-Fang Wu Ph.D.
Professor
Biology

Major research interests in this laboratory concern the genetic control of function and development of the nervous system. Currently we focus on mutants of the fruit fly Drosophila with altered nerve excitability and deficiencies in learning behavior.  The effects of single-gene mutations and their interactions in double mutants provide clues for the functional organizations of the ionic channels and second messenger pathways that govern neuronal activities and synaptic plasticity.
Mutant alleles and conditional expression of transients are analyzed to elucidate experience-dependent plasticity in the development of the functional organization in the nervous system. The effects of altered nerve activity and physiological actions on the path finding, arborization, and generation of neural connectivities are determined in neuronal cultures as well as in genetic mosaics.

Research Modes

Experimental

Research Paradigms

Cellular Signalling Pathways, Gene-environment Interactions and Interplay, Genetic Engineering, Imaging, Mutation, Protein-protein Interactions, Translation and Post-translational Modifications

Applications

Ageing, Behavior and Mental Disorders, Nervous System

Organisms

Drosophila
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