Research Interests

Vitamin D maintains calcium homeostasis and is required for bone development and maintenance. Recent evidence has indicated an interrelationship between vitamin D and health beyond bone including effects on preventing or at least partially protecting against certain autoimmune diseases including diabetes and multiple sclerosis. Exactly how vitamin D affects numerous different systems is a subject of continuing investigation. New developments in our lab related to the function and regulation of vitamin D target proteins have provided novel insights into the mechanisms of vitamin D action. The vitamin D regulated calcium binding protein calbindin has been reported to be a facilitator of calcium diffusion in the intestine and in the kidney where it has been suggested to be involved in the enhancement by 1,25(OH)2D3 of distal tubular calcium reabsorption. Studies in our lab have shown that calbindin also has an important role in protecting against apoptotic cell death in different tissues including protection against cytokine destruction of osteoblastic cells and pancreatic beta cells. These findings have important implications for therapeutic intervention of many disorders including diabetes and osteoporosis. Recent studies in our laboratory of intestinal calcium absorption using calbindin-D9k null mutant mice as well as mice lacking the 1,25(OH)2D3 inducible epithelial calcium channel present in the intestine, TRPV6, provide evidence for the first time of calbindin-D9k and TRPV6 independent regulation of active intestinal calcium absorption, thus suggesting that other yet unidentified proteins are also important in the process of 1,25(OH)2D3 mediated active intestinal calcium absorption. In the kidney, in addition to enhancing the distal tubular reaborption of calcium, the other important effect of 1,25(OH)2D3 is its ability to regulate its own production by suppressing 25(OH)D3 1 alpha hydroxylase and by stimulating the renal 25(OH)D3 24 hydroxylase (24(OH)ase) which is involved in the catabolism of 1,25(OH)2D3. In our laboratory we have identified various factors that cooperate with the vitamin D receptor in regulating 25(OH)ase expression including C/EBP beta, SWI/SNF (complexes that facilitate transcription by remodeling chromatin using the energy of ATP hydrolysis) and CARM1, an arginine methyltransferase. Our findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)2D3 mediates its multiple biological effects. An understanding of these mechanisms may lead in the future to the design of analogs of 1,25(OH)2D3 designed to selectively modulate specific responses in specific target tissues. These analogs may be used to treat autoimmune disorders and various types of cancer as well as bone loss disorders.

Publications