Anne E Kwitek Ph.D. [Former faculty]

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: 

Thomas H Wassink M.D.

Current
Thomas
H
Wassink
M.D.
Professor
Psychiatry
Research area(s): 
Human Genetics
Address
Research
Research Focus: 

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.

Faculty affiliations: 

Richard J Smith M.D.

Current
Richard
J
Smith
M.D.
Professor and Vice Chair
Otolaryngology
Research area(s): 
Human Genetics
Address
Research
Research Focus: 

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.

Faculty affiliations: 

Todd E Scheetz Ph.D.

Current
Todd
E
Scheetz
Ph.D.
Professor
Ophthalmology and Visual Sciences
Research area(s): 
Ophthalmology and Visual Sciences
Address
3185
MERF
3185
MERF
Research
Research Focus: 

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.

Faculty affiliations: 

Jeff C Murray M.D.

Current
Jeff
C
Murray
M.D.
Professor
Pediatrics
Research area(s): 
Developmental Genetics; Human Genetics
Address
2182
ML
2182
ML
Research
Research Focus: 

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.

Faculty affiliations: 

Paul B McCray M.D.

Current
Paul
B
McCray
M.D.
Professor
Pediatrics
Research area(s): 
Human Genetics; Molecular and Biochemical Genetics
Address
6320
PBDB
6320
PBDB
Research
Research Focus: 

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.

Faculty affiliations: 

Aloysius J Klingelhutz Ph.D.

Current
Aloysius
J
Klingelhutz
Ph.D.
    Professor
    Microbiology
    Research area(s): 
    Biology and Genetics of Human Cancer and Aging
    Address
    2202
    MERF
    2216
    MERF
    Research
    Research Focus: 

    Our research has diversified into two main areas: 1) How viruses infect and disseminate in skin; 2) How microbial and environmental factors play a role in the development of metabolic syndrome. Our prior research addressed how human cells senesce, leading to aging, and how they become immortal, leading to cancer, with a particular interest in on how human papillomaviruses transform cells. Our expertise in cell immortalization and cell culture techniques has allowed us develop 3D cell culture models that recapitulate human tissue for our research. 

    1) How viruses infect and disseminate in skin. Collaborative studies were recently initiated with Wendy Maury’s lab to examine how Ebola virus (EBOV) infects and transmits through human skin. We found that EBOV can infect and replicate in different skin cell populations. We are currently working to understand the course of infection in skin, what specific receptors are being utilized by EBOV in skin cells, and what role skin infection plays in transmission and pathogenesis.

    2) How microbial and environmental factors play a role in the development of metabolic syndrome. Our success with immortalizing human preadipocytes (pre-fat) cells has led to studies on how environmental and bacterial toxins cause or exacerbate type II diabetes through effects on fat tissue. We found that dioxin-like polychlorinated biphenyls (PCBs), which are persistent organic pollutants, can disrupt adipogenesis (i.e. the development of functional fat cells) through activation of the aryl hydrocarbon receptor (AhR). This causes a proinflammatory response and inhibits master regulatory genes involved in adipogenesis. Endogenous microbial-derived tryptophan metabolites are also able to activate AhR. Studies are underway to determine the mechanism by which AhR activation disrupts adipogenesis and to develop 3D cultures and in vivo genetic models to assess the role of AhR in the development of metabolic syndrome.

    Anne E Kwitek Ph.D.

    Associate Professor, Pharmacology & Internal Medicine
    Associate Director, Iowa Institute of Human Genetics

    John H. Fingert M.D., PhD.

    Current
    John
    H.
    Fingert
    M.D., PhD.
    Professor
    Ophthalmology and Visual Sciences
    Research area(s): 
    Molecular Genetics of Glaucoma and other inherited eye diseases
    Address
    3125
    MERF
    3111B
    MERF
    Research
    Research Focus: 

    I am a board-certified ophthalmologist with fellowship training in glaucoma and I have a Ph.D. in ophthalmic genetics. My training and experience has provided me with broad clinical and laboratory expertise to investigate the genetic basis of optic nerve disease. My early research resulted in the detection of the first glaucoma gene, myocilin, and more recently my laboratory has discovered one of two known normal tension glaucoma genes, TBK1. My laboratory is currently investigating the mechanisms by which defects in genes in the autophagy pathway (TBK1, OPTN, and others) lead to normal tension glaucoma using transgenic mice, induced pluripotent stem cells, and other patient-based studies. Other major projects include genetic studies of pigmentary glaucoma, exfoliative glaucoma, dominant optic atrophy, and studies of the genetic basis of quantitative features of glaucoma (eye pressure, corneal thickness, and optic nerve cupping). These projects are part of an overall mission to investigate the genetic basis of optic nerve disease and develop sight-saving therapies for this common group of blinding diseases.

     

    Faculty affiliations: 

    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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