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The long-term goal of my research is to understand how regulation of lipids (cholesterol, saturated versus unsaturated fatty acids) and glucose affect the pathogenesis of cardiovascular disease and diabetes through the use of cultured primary hepatocytes (human, mouse), gene-ablated, overexpression, and humanized mice as models for understanding human conditions, and to use these discovered mechanisms to exploit new drug development. Our current projects include investigating whether an intracellular fatty acid binding protein L-FABP mediates fibrate signaling to hepatic PPAR alpha, an action potentiated by high glucose. Further, we propose that the human L-FABP T94A gene variant is impaired in its ability to function in this pathway, especially in the context of high glucose. We will be examining the collective physiologic impact of fibrates and human L-FABP T94A variant on signaling to PPAR alpha in a humanized mouse model in vivo. The impact of human L-FABP T94A variant and glucose on fibrate nuclear targeting for PPAR alpha interaction and activation is being examined via primary cultured human hepatocytes of WT and variant cells. I have the expertise, productivity, and interest needed to successfully carry out the proposed work. I am Director of a Transgenic Mouse Core Facility, and supervise the Injection and Morphology/Pathology Sections. I have a broad background in animal models, with specific training and expertise in key research areas in this application, including immunocytochemistry, primary hepatocyte culture, cell culture, construction of mammalian expression vectors, transfection, cloning of cells, in vivo lipid metabolism, and mouse phenotyping. As a Resident in Laboratory Animal Medicine and Postdoctoral Fellow in Comparative Pathology at the University of Missouri, I was trained in both human and laboratory animal pathology (comparative, experimental pathology) as well as earning Diplomate status in the American College of Laboratory Animal Medicine (ACLAM). At the University of Cincinnati Health Sciences Center, I furthered my expertise in animal models by learning gene-ablation techniques in the laboratory of Thomas Doetschman, collaborating on several NIH PO1 project grants as well as my own RO1 grants to clone the mouse gene coding for Hageman Factor and develop a genetically deficient mouse model. As Director of Comparative Pathology while teaching human pathology, I developed collaborations with Tom Doetschman, Steve Potter, Peter Stambrook, Jeffrey Robbins and other experts in the newly expanding field of mouse gene targeting to strengthen my expertise in mouse phenotyping and pathology, having PO1 components on 3 grants as well as PI and Co-I on RO1 grants, and publishing in Nature, Cell, J Biological Chemistry, and other high impact journals. While at Texas A&M University, I applied this expertise to develop and phenotype new mouse models overexpressing or ablated in genes encoding fatty acid and fatty acyl CoA binding proteins in collaboration with Dr. Friedhelm (Fred) Schroeder. The highly productive integration of different disciplines with the Dr. Friedhelm is particularly unique in our ability to follow key questions from the in vitro isolated protein level (Schroeder), through live cell culture imaging experiments (Schroeder and Kier), and in vivo into the molecular biological and physiologic environment of mouse models (Kier).
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