Unraveling the ligand-independent signaling of the vitamin D receptor

Vitamin D is a major regulator in the maintenance of stable serum calcium concentrations by enhancing the absorption of food-derived calcium in the intestine. In conditions of insufficient calcium supply, vitamin D will induce calcium resorption from the bone, a major calcium storage site, thereby reducing skeletal integrity. Therefore, vitamin D and/or calcium supplementation are used as standard therapy in osteoporosis. However, the dose of vitamin D and the need for simultaneous calcium supplementation is still discussed as the complex network that regulates calcium homeostasis is not fully understood. In the current project we aim to identify and characterize novel target genes critically involved in calcium homeostasis. We take the unique approach of using a model in which the vitamin D receptor (VDR) is mutated so that it cannot alter gene expression upon vitamin D binding. This will allow to investigate the effects of the VDR itself, independent of the vitamin D hormone. We will first investigate the physiological role of vitamin Dindependent signaling in classical vitamin D target tissues with a major emphasis on bone. Subsequently, we will study the genome wide binding of this mutant VDR and investigate which genes are repressed in different target organs. We believe that this approach will provide valuable insight in the regulation of calcium homeostasis and may ultimately lead to improved treatment strategies in osteoporosis.