Vitamin D receptor signaling: (Coactivator-independent) effects in mineral and bone homeostasis

Unraveling the ligand-independent signaling of the vitamin D receptor. The parathyroid hormone (PTH)/vitamin D axis is a major regulator in the maintenance of stable serum calcium concentrations, which is of utmost importance to ensure normal cellular and organ function. Subtle changes in circulating calcium concentrations cause an increase in the secretion of PTH which will, in turn, increase renal calcium reabsorption, enhance calcium efflux from bone and will stimulate the production of 1,25-dihydroxyvitamin D3, the active form of vitamin D3, that exerts its action by binding to the vitamin D receptor (VDR). The first major objective of this project is to delineate the physiological importance of the ligand-independent effects of VDR in parathyroid, intestine, kidney and bone. The second objective is to assess whether ligand-independent VDR signaling affects bone directly by the use of three different approaches. Those approaches will include the study of in vitro osteoblast and osteoclast cultures, the establishment of mice that express a mutant VDR∆AF2 protein in osteoprogenitors and finally the treatment of Vdr∆AF2 mice with Cinacalcet to circumvent confounding effects of PTH on bone. The third objective is to identify and characterize novel genes that are involved in calcium homeostasis by the use of a combined RNA-seq and ChIP-seq approach.