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Thurl
Harris
Degree(s): Ph.D. Graduate School: Baylor College of Medicine Primary Appointment: Assistant Professor of Pharmacology Research Interests: Molecular mechanisms controlling insulin signaling and fat synthesis. Email Address: teh3c@virginia.edu |
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Biomedical Sciences Graduate Program(s) Research Description As Paleolithic hunter gatherers, the human diet was relatively low in fats and simple carbohydrates. Technological advances, beginning with the agricultural revolution 12,000 years ago and culminating with the mechanization of food production in the last century, have provided a significant portion of the world’s population with access to inexpensive, energy-dense food. In the modern age the ready availability of carbohydrates and fats, combined with a large reduction in physical labor, has lead to a predictable rise in obesity. As an underlying risk factor for type II diabetes and cardiovascular disease, understanding how obesity promotes the development of these diseases is of extreme importance for worldwide health. Food intake triggers the release of insulin, an anabolic hormone that promotes nutrient storage and protein synthesis. Mechanisms underlying the storage of carbohydrates and fats as triacylglycerol (TAG) in adipose tissue and the dysregulation of insulin signaling that occurs during obesity are the primary focus of the laboratory. Triacylglycerol Storage in Adipocytes and Inflammation – An important research interest in the laboratory are the enzymatic pathways by which adipocytes store fatty acids as TAG, and the functional consequences of excess TAG storage. Lipin 1 is a Mg2+-dependent phosphatidic acid phosphatase that performs the next to last enzymatic step in TAG synthesis, the dephosphorylation of phosphatidic acid to diacylglycerol. How lipin 1 activity is regulated in adipocytes by insulin is a key component of our studies. Complementary research in the laboratory investigates the link between lipin 1 and inflammation. As adipocytes accumulate increasing amount of TAG during obesity (hypertrophy) they activate inflammatory pathways that lead to macrophage infiltration of adipose tissue and adipocyte dysfunction. We are actively pursuing both the involvement of lipin 1 in the mechanisms that initiate inflammation in adipocytes as well as changes in lipid metabolites that occur during the development of adipocyte hypertrophy. The mTOR Signaling Pathway - A key player in the insulin signaling cascade is the mammalian target of rapamycin (mTOR), a highly conserved Ser-Thr phosphatidylinositol 3-kinase-related protein kinase that integrates cellular energy status and growth factors to regulate cellular growth, survival, and metabolism. mTOR forms two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) each of which catalyzes the phosphorylation of different substrates in response to insulin. The rapamycin sensitive mTOR complex (mTORC1) contains mTOR, raptor, PRAS40 and LST8, while the rapamycin insensitive mTOR complex (mTORC2) contains mTOR, rictor, LST8 and Sin1. Under conditions of caloric excess, such as that seen during diet-induced obesity, both arms of the mTOR pathway can be inhibited. We study the molecular mechanisms of how insulin signaling activates the two different mTOR complexes, the functional consequences of mTOR activation, and how these complexes are inhibited during obesity. Selected Publications Intranet Profile [To add/update Intranet profile information, read these instructions.]
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