Faculty
Lori Wallrath Ph.D.
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.
Thomas H Wassink M.D.
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.
David S Weiss Ph.D.
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.
Michael J Welsh M.D.
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..
Mary E Wilson M.D.
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.
Chun-Fang Wu Ph.D.
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.
