Pedro Gonzalez-Alegre M.D. [Former faculty]

Markus H Kuehn Ph.D.

Current
Markus
H
Kuehn
Ph.D.
Professor
Ophthalmology and Visual Sciences
Research area(s): 
Genetics of Optic Neuropathies
Address
4120F
MERF
4120
MERF
Research
Research Focus: 

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.

Faculty affiliations: 

Chun-Fang Wu Ph.D.

Current
Chun-Fang
Wu
Ph.D.
Professor
Biology
Research area(s): 
Neurogenetics of Drosophila
Address
237
BB
231
BB
Research
Research Focus: 

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.

Faculty affiliations: 

John R Manak Ph.D.

Current
John
R
Manak
Ph.D.
Associate Professor
Biology
Research area(s): 
Genetic basis of human disease using high-throughput genomics methodologies, fruit fly models of human disease and cancer.
Address
459A
BB
455=9A
BB
Research
Research Focus: 

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.    

Faculty affiliations: 

Daniel F Eberl Ph.D.

Current
Daniel
F
Eberl
Ph.D.
Professor
Biology
Address
Research
Research Focus: 
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.

Curt D Sigmund Ph.D.

Professor
Pharmacology

Andy F Russo Ph.D.

Current
Andy
F
Russo
Ph.D.
Professor
Molecular Physiology & Biophysics
Research area(s): 
Eukaryotic Gene Expression; Molecular and Biochemical Genetics
Address
5-432
BSB
5-433
BSB
Research
Research Focus: 

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.

Toshihiro Kitamoto Ph.D.

Current
Toshihiro
Kitamoto
Ph.D.
Associate Professor
Anesthesia
Research area(s): 
Nervous System and Genetic Variation
Address
1-316
BSB
1-376
BSB
Research
Research Focus: 

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.

Faculty affiliations: 

Pedro Gonzalez-Alegre M.D.

Assistant Professor.
Neurology

Michael G Anderson Ph.D.

Current
Michael
G
Anderson
Ph.D.
Professor
Molecular Physiology & Biophysics
Research area(s): 
Human Genetics; Molecular and Biochemical Genetics
Address
Research
Research Focus: 

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.

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