Regulation of minerals and fluids excretion in vitamin D

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DESCRIPTION (adapted from the application) Yan Chun Li, Ph.D., received a Ph.D. degree in biochemistry from Kent State University. After postdoctoral training at MIT and Harvard Medical School, he joined the University of Chicago as an Assistant Professor of Medicine. Dr. Li's long-term career goal is to develop into a leading independent investigator in the field of vitamin D research, with a long-term objective of understanding the physiological functions of the vitamin D endocrine system. As Dr. Li has no formal physiology training, the proposed five-year career development plan will allow him to receive extensive training on general physiology of the vitamin D endocrine system and the pathophysiology of vitamin D deficiency, particularly, in the area of vitamin D regulation of mineral metabolism. The sponsor of the present application, Dr. Brasitus, is an international authority on vitamin D signaling in normal and tumor cells. The Research Advisory Board, formed by Drs. Brasitus, Sitrin, Favus and Graves, is a group of internationally renowned physician-scientists with extensive research experience and expertise in the field of vitamin D research, and will provide collaboration and advice in Dr. Li's ongoing research. Dr. Li's research plan is to study the regulation of renal excretion of calcium, sodium and body fluid by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], using the vitamin D receptor (VDR) null mouse model. Studies will be focused on renal calbindin-D9k (CaBP-D9k), the rate-limiting protein involved in transcellular calcium transport, and atrial natriuretic peptide (ANP), a heart-derived hormone that promotes sodium and water excretion. The first aim is to study the effect of VDR inactivation, 1,25(OH)2-vitamin D deficiency, and dietary calcium on the expression of renal CaBP-D9k and its role in calcium reabsorption. The second aim is to study the regulation of renal CaBP-D9k expression by 1,25(OH)2D3, as well as the modulation of 1,25(OH)2D3-induced CaBP-D9k expression by PTH or calcium, using VDR(+/+) and (-/-) primary renal tubule cell cultures. This in vitro culture system will also be used to analyze the CaBP-D9k gene promoter and identify the vitamin D response element. The third goal is to study the effect of VDR inactivation on ANP expression and sodium and body fluid balance, in order to test in vivo, the hypothesis that 1,25(OH)2D3 negatively regulates ANP expression.