I hypothesize that age related changes in calcium homeostasis are functionally linked to the expression of the apical calcium channel present in the intestine TRPV6. Alterations of the vitamin D endocrine system and 1,25(OH)2D3 regulated TRPV6 with age results in a deterioration of the normal adaptive response to inadequate calcium intake or to calcium need. With advancing age, effective calcium deficiency as a result of faulty 1,25(OH)2D3 regulated TRPV6 may become more and more important leading to age related bone loss aggravated by calcium deficiency. In order to test this hypothesis, the following specific aims are proposed. 1.) To examine the effects of age and gender on intestinal calcium absorption in the TRPV6 knock out (KO) mouse. Compensatory and reciprocal mechanisms involved in the alterations in calcium homeostasis in the TRPV6 KO mouse will also be examined. How the absence of this protein with age in male and female mice may be related to changes in bone mineralization will also be assessed. 2.) to examine the effects of age and gender on 1,25(OH)2D3 regulated intestinal calcium absorption and on active calcium transport under low dietary calcium conditions in the TRPV6 KO mouse. 3.) To determine the mechanisms involved in the regulation of TRPV6 by 1,25(OH)2D3.; Experiments proposed in this application will give insight for the first time into the in vivo role of TRPV6. This knowledge may be relevant to understanding age related bone disease and ultimately may lead to the translational development of important adjunct drugs able to help prevent osteoporosis.
