| Paul A. Dawson
Associate Professor of Internal Medicine (Gastroenterology)
Associate Professor of Pathology (Comparative Medicine)
B.S., 1981 University of Florida - Gainesville,
Ph.D., 1986, State University of New York - Stony Brook |
My lab is focused on identifying the genes responsible for maintenance of the enterohepatic circulation and elucidating the mechanisms responsible for their regulation under normal and pathophysiological states. Specific Ongoing Projects 1. Molecular Mechanism of Primary Bile Acid Malabsorption The ileal bile acid transporter is thought to be the major mechanism responsible for the intestinal absorption of bile acids. In order to understand the role of the ileal bile acid transporter in normal physiology and the pathophysiology of GI and lipid disorders, we have generated an ileal bile acid transporter knockout mouse. This unique model of primary bile acid malabsorption is beginning to provide new insights to the relationships between bile acid and lipid metabolism. 2. Molecular Mechanism of Primary Bile Acid Malabsorption Unlike ileal bile acid absorption, the mechanism responsible for bile acid export across the basolateral membrane is poorly understood. We recently used a transcriptional profiling approach employing the ileal bile acid transporter knockout mice to identify the ileal basolateral bile acid transporter, Ost-Ost, an important missing link in our understanding of the enterohepatic circulation of bile acids. Studies are underway to understand the mechanism and regulation of the ileal basolateral bile acid transporter. Potential New Projects Bile Acids and Colon Cancer - A new project in the lab involves the relationship between bile acids, vitamin D, and colon cancer. Bile acids have been proposed to act as tumor promoters in the colon. In fact, dietary fiber is thought to be protective against colon cancer by physically binding bile acids in the colon and preventing their interaction with colonocytes. It has also been proposed that Vitamin D protects against colon cancer by inducing the colonic catabolism of bile acids. The data for this hypothesis is derived largely from epidemiological studies and the hypothesis has not been rigorously tested. However, this has not kept the model from being widely quoted (for example, see Science 296, 1313-1316, 2002). We have recently generated an ileal bile acid transporter knockout mouse. This mouse is the only animal model with a pure bile acid malabsorption (the previous studies used animals with partially resected small intestines, a model of short bowel syndrome). We are studying colonic crypt hyperplasia in this model as well as crossing the ileal bile acid transporter knockout into colon cancer susceptible backgrounds such as the Apc+/- mouse to test this hypothesis.
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Recent Publications (selected): 1. Belinsky MG, Dawson PA, Shchaveleva I, Bain LJ, Wang R, Ling V, Chen ZS, Grinberg A, Westphal H, Klein-Szanto A, Lerro A, Kruh GD.Analysis of the in vivo functions of Mrp3. Mol Pharmacol. 2005 Jul;68(1):160-8. 2. Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, Ballatori N. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem. 2005 Feb 25;280(8):6960-8. 3. Harris MJ, Kagawa T, Dawson PA, Arias IM. Taurocholate transport by hepatic and intestinal bile acid transporters is independent of FIC1 overexpression in Madin-Darby canine kidney cells. J Gastroenterol Hepatol. 2004 Jul;19(7):819-25. |