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Mentor	Project(s)
Douglas Andres	1) Regulation of Neuronal Survival by the Rit GTPase Aberrant cell death contributes to various neurodegenerative disorders including stroke, epilepsy, and Alzheimer's disease. We have discovered a novel group of proteins (Rit and Rin) that promote neuron survival. We have generated transgenic mouse expressing these proteins within the brain, and find that the animals are resistant to neurological disease, while targeted knockout of the Rit protein increases neuronal cell death. Through the combined use of biochemistry, molecular biology, and genetic approaches, we hope to understand the pathways that are used to Rit neurons to survive with the goal of applying this knowledge toward the treatment of neurodegenerative disease. 2) Regulation of Calcium Signaling in the Heart Voltage-dependent calcium channels (VDCCs) regulate the flow of Ca2+ ions across cellular membranes to regulate a variety of cellular functions, including heart muscle contraction, hormone secretion, and nerve transmission. We have recently identified a novel group of proteins (including Rem, Rem2, Rad, and Gem) that regulate voltage-dependent Ca2+ channel function. A series of transgenic mice that lack members of this protein family have been created, and develop disorders as diverse as defective insulin secretion, tachycardia, and cardiac hypertrophy. We wish to understand the cellular role of these proteins with the hope that they will provide a unique approach to treating diseases as diverse as heart failure and diabetes.
Luke Bradley	Central nervous system protein recognition and specificity The properties that govern protein-protein interactions and specificity will be examined. A modified central nervous system protein's structure and function will be characterized by using - but not limited to - fluorescence and circular dichroism spectroscopies. Results will contribute towards understanding the basis of the native protein's function.
Young-In Chi	Structural analysis of protein/DNA complexes by X-ray crystallography X-ray crystallography is a technique that allows us to see the atomic details of biological macromolecules in action. Our lab uses this technique in conjunction with other biochemical/biophysical and cellular studies to understand the molecular basis of gene regulation and its defects found in human diseases such as diabetes and cancer. The prospective student will help us by carrying out his/her own project that involves various experimental routines such as preparation and characterization of protein/DNA complexes, crystallization, X-ray diffraction data collection, and computations to solve/analyze our structures and other structures available in the public database.
Trevor Creamer	Characterization of intrinsically-disordered proteins Over the last decade a new class of proteins, known as intrinsically disordered, has been identified. These often do not fold into a defined structure until they bind a target molecule. The prospective student will use a variety of techniques to help us express, purify, and characterize the physical behavior of calcineurin, a vital phosphotase whose critical regulatory domain is disordered until bound by by the calcium-sensing protein calmodulin.
Rebecca Dutch	Modulating the activity of paramyxovirus fusion proteins Viral fusion proteins promote fusion of the viral membrane with the host cell membrane. We have identified a region that we hypothesize is critical for controlling triggering of fusion. This project will involve introducing mutations into a viral fusion protein and analyzing the effect of the mutation on membrane fusion activity.
Steven Estus	RNA splicing of genes related to cholesterol homeostasis and Alzheimers disease The goal of this project is to (i) identify novel splice variants in mRNAs encoding proteins implicated in cholesterol homeostasis and Alzheimers disease and (ii) evaluate the role of genetics, splicing factors and Alzheimers disease in generating these splice variants by correlating their quantities with variations in DNA sequence, levels of relevant splicing factors, and disease status. Hence, we seek to identify novel factors that modulate brain cholesterol and Alzheimers disease risk.
Michael Fried	Mechanisms of DNA repair DNA repair is essential for normal development and heredity. In addition, many cancers are thought to arise as a result of faulty or absent repair activities. Repair enzymes must locate damaged sites embedded in a very large excess of normal DNA. To help determine how damaged sites are located, the prospective student will use molecular and biophysical methods to characterize the DNA-interactions of an important human repair enzyme.
Matthew Gentry	Use of multiple models to understand epilepsies and neurodegeneration Lafora disease (LD) is an autosomal recessive, neurodegenerative epilepsy that results in the death of the patient by age 25. A hallmark of LD is the accumulation of insoluble carbohydrates in the cytoplasm of cells, these accumulations are called Lafora bodies. While Lafora bodies are found in most all cell types of LD patients they only cause cell death in neurons. Our lab focuses on determining the molecular mechanism of this disease by using mouse, tissue culture, invertebrate, and protozoan (single-cell eukaryotes) models. 1) Develop a biochemical assay to test which enzyme is defective in LD patients. 2) Develop and characterize a protozoan model of LD.
Harry LeVine	Ligand binding to domains of the Receptor for Advanced Glycation Endproducts (RAGE) RAGE is a member of the Scavenger Receptor family of proteins which process multiple ligands and also participate in cellular signaling pathways. RAGE in the choroid plexus transports soluble forms of Abeta out of the brain into the periphery but also transduces the Abeta toxic signal to neurons in the rest of the brain. This project will investigate the roles of defined structral domains of RAGE in binding ligands enriched in Alzheimer's disease brain compared to age-matched normal brain.
Andrew Morris	Role of cell surface receptors in atherothrombotic disease Projects can involve clinical, preclinical (animal) or cell-based models and experimental systems. Research in our laboratory would be of broadly relevant to anyone considering postgraduate training in biomedical research but of particular interest to students considering an MD/Ph.D. program.
Paul Murphy	Mechanistic connections between diabetes and Alzheimer's disease Both type II diabetes (DM2) and Alzheimer's disease (AD) are significant public health problems. It has been known for several years that mid-life DM2 confers significant risk for the development of AD in later years. Our lab has recently made some exciting advances in mapping out some of the basic molecular processes that may underly this link. This project will use techniques in biochemistry, cellular and molecular biology to explore this linkage in cultured cells, particulary in primary neurons.
Sabire Ozcan	1) Identification of miRNAs regulated by glucose miRNAs are small RNA molecules that regulate translation in cells and have been implicated to play a role in many diseases. Since glucose is the major carbon and energy source for most organisms, the major goal of this project to identify miRNAs that are up- or down-regulated by glucose in order to study their function in glucose metabolism. 2) Role of O-linked glycosylation in cell function O-linked glycosylation of proteins is important for cell function. Our recent data indicate that O-linked glycosylation functions as a sensor of intracellular glucose levels and regulate many important processes in the cell. The long-term goal of this project is to understand how O-linked glycosylation of proteins is linked to glucose sensing.
David Rodgers	1) Neuropeptidase function Understanding the basis for broad substrate recognition in neuropeptidases, enzymes that metabolize peptides used to transmit signals between cells in the nervous system and other tissues. Development of drugs that target these enzymes as therapeutics for disorders of the nervous system and pain relief. 2) Choline acetyltransferase Exploring the mechanism by which congenital mutations affect the function of choline acetyltransferase, the enzyme that makes the neurotransmitter acetylcholine, to cause motor diseases. The significance of the poorly folded structure of the enzyme will be investigated as an approach to developing therapies for the treatment of the associated disorders.
Stefan Stamm	Role of small RNAs in the Prader-Willi syndrome The Prader-Willi syndrome is the most frequent inherited cause for obesity and type II diabetes. Genetic evidence shows that the disease is caused by the loss of small nucleolar RNAs. We recently showed that some of these small nuleolar RNAs function in alternative splice site selection. The project aims to identify new targets of these small nucleolar RNAs and to understand their mechanism of action.
Craig Vander Kooi	Role of cell surface receptors in new blood vessel formation New blood vessel formation (angiogenesis) is critical during development and wound repair. The project involves understanding the basis for ligand/receptor interactions which stimulate angiogenesis using structural probes. Tumor angiogenesis is also required for the growth of many types of solid tumors and we are also exploring novel anti-angiogenic strategies.
David Watt	1) Synthesis of reagents for analyzing fatty acids his project involves the laboratory synthesis of various reagents useful in analyzing fatty acids and phosphatidic acids. It involves first the application of organic synthesis and secondly, assuming the first part goes well, their application to biochemical problems of interest. 2) Synthesis of reagents for studying spliceosome function This project involves the laboratory modification of natural products useful in studying spliceosome function.
Wally Whiteheart	Charaterization of platelet secretion machinery and underrstanding Arf6 in resting platelets Blood platelets are small anucleated cell fragments that play a key role in blood clotting. Clinically, anti-platelet drugs are critical for controlling inappropriate clot formation and preventing strokes and heart attacks. Projects in the lab focus on understanding the mechanisms of platelet activation and secretion. Specific projects will involve the detailed analysis of platelets from genetically altered mice that lack specific elements of the secretory machinery. These studies will also use reconstitution assays to determine the specific steps that are defective. Other projects will focus on the role of the small GTP binding protein Arf6 in platelet activation.
Haining Zhu	Protein misfolding response in Lou Gehrig's disease The goal of this project is to determine how the protein misfolding response pathways are activated by the SOD1 mutants that are linked to Lou Gehrig's disease. We will examine the expression levels of several key proteins involved in protein misfolding response. We will also characterize the signaling pathways downstream of protein misfolding response to determine how SOD1 mutants cause cellular damages and neuronal degeneration.