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 | John Baxter, M.D.
Professor The metabolic syndrome is a constellation of diseases that includes obesity, insulin resistance and type II diabetes, high blood pressure and alterations in cholesterol and fat metabolism. This syndrome (also known as Syndrome X) represents one of the largest health threats to the western world today. Treatments for individual components of the syndrome will be very useful in their own right, but also have the potential to influence other facets of this inter-related disease. For example, treatments that reduce obesity should also reduce the risk of developing Type II diabetes. Understanding the signals that regulate normal metabolism, blood pressure and cholesterol and fat levels should yield insights into the pathogenesis of metabolic syndrome and lead to novel treatments for the disease. Our laboratory has focused upon endocrine signals that regulate metabolism, and we have made contributions in different areas including the cloning and expression of human growth hormone, the mechanisms that restrict growth hormone expression to the pituitary and the molecular signals that constitute the renin-angiotensin system. Our major current focus is on thyroid hormone, which regulates overall metabolic rate, heart function and cholesterol and triglyceride levels, amongst many other functions. Elevated levels of thyroid hormones lead to increases in metabolic rate and concomitant rapid weight loss and also improve cholesterol and triglyceride balance. However, undesirable effects, including increased heart rate and arrhythmias, temper these potentially desirable effects. One of our goals is to develop selective analogs that specifically elicit beneficial effects on metabolic parameters and body weight in the absence of effects on heart rate. These compounds should represent novel treatments for obesity and have the potential to reduce the risk of Type II diabetes. Our group, in collaboration with Dr. Robert Fletterick in the Department of Biochemistry and Biophysics at UCSF, obtained the first X-ray crystallographic models of the hormone binding domains of both thyroid hormone receptor proteins. These structures yield insights into thyroid hormone action and are prototypes for understanding related nuclear receptors, many of which play key roles in the metabolic syndrome, cancer and many other diseases. We use the structures for systematic placement of mutations to analyze receptor function and have uncovered the ways that the receptors repress and activate gene transcription, dimerize and bind hormone. The structures also facilitate the design of thyroid hormone receptor ligands (in collaboration with Dr. Tom Scanlan in the Departments of Pharmaceutical Chemistry and Molecular and Cellular Pharmacology at UCSF). We have identified receptor isoform specific drugs that elicit highly desirable profiles in animal models, and the first thyroid hormone antagonists. Our present efforts include use of structural models to understand the molecular mechanisms of novel selective pharmaceuticals and the specificity of receptor interactions with coregulators. We are also attempting to obtain crystal structures of larger fragments of the thyroid receptor to understand how hormone influences other regions of the protein and its DNA binding activities. Other interests include research into the actions of related steroid receptors (including those for androgens and aldosterone) that play important roles in regulation of metabolism and blood pressure. Selected Publications: Webb, P., Nguyen, N.H., Chiellini, G., Yoshihara, H.A., Cunha Lima, S.T., Apriletti, J.W., Ribeiro, R.C., Marimuthu, A., West, B.L., Goede, P., Mellstrom, K., Nilsson, S., Kushner, P.J., Fletterick, R.J., Scanlan, T.S., and Baxter, J.D. Design of thyroid hormone receptor antagonists from first principles. J Steroid Biochem Mol Biol 83: 59-73 (2002). Ribeiro, R.C., Feng, W., Wagner, R.L., Costa, C.H., Pereira, A.C., Apriletti, J.W., Fletterick, R.J., and Baxter, J.D. Definition of the surface in the thyroid hormone receptor ligand binding domain for association as homodimers and heterodimers with retinoid X receptor. J Biol Chem 276: 14987-95 (2001). Baxter, J.D., Dillmann, W.H., West, B.L., Huber, R., Furlow, J.D., Fletterick, R.J., Webb, P., Apriletti, J.W., and Scanlan, T.S. Selective modulation of thyroid hormone receptor action. J Steroid Biochem Mol Biol 76: 31-42 (2001). Feng, W., Ribeiro, R.C.J., Wagner, R.L., Nguyen, H., Apriletti, J.W., Fletterick, R.J., Baxter, J.D., Kushner, P.J., and West, B.L. Hormone-Dependent Coactivator Binding to a Hydrophobic Cleft on Nuclear Receptors. Science 280: 1747-9 (1998). Wagner, R.L., Apriletti, J.W., McGrath, M.E., West, B.L., Baxter, J.D., and Fletterick, R.J. A structural role for hormone in the thyroid hormone receptor. Nature 378: 690-7 (1995).
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