Exploring the role of intestinal cell metabolism and gastro-intestinal hormones in calcium homeostasis and pathology.

Adequate intestinal calcium absorption is essential to prevent bone loss caused by aging or pathologies. Calcium and vitamin D supplementations are therefore widely used, but this therapy is still confronted with issues of safety, compliance and limited efficacy. Using several transgenic mouse strains, we observed that vitamin D supplementation without adequate intestinal calcium transport has deleterious effects on bone. Novel therapeutic strategies are thus required which necessitates thorough mechanistic insight in intestinal calcium absorption. We will therefore use the following multidisciplinary hypothesisdriven approach with translational outcome. We postulate that vitamin D-regulated intestinal calcium transport is linked to cellular energy metabolism,  transport of other nutrients and buffering in the endoplasmatic reticulum. We will use a candidate gene approach and a screening approach to identify the proteins involved. Next, analysis of calcium and vitamin D homeostasis in preclinical mouse models of gastric bypass surgery and chronic kidney disease will advance the translation of these findings to the clinic. Finally, we postulate that calcium transport is already sensed in the gut and that the release of gastrointestinal hormones will initiate adaptive responses to preserve normocalcemia. A peptidomics approach will be used. We are confident that insight in the mechanisms by which calcium is sensed and transported in the intestine is a crucial step towards the optimization of current therapies and/or the development of novel ones.