My research investigates signal transduction, molecular structures, and pathophysiological actions of the extracellular calcium-sensing receptor (CaSR) and its associated signaling molecules in controls of systemic mineral and skeletal homeostasis and more recently in the induction of brain diseases and explores the therapeutic potential of the receptor to treat several prevalent diseases afflicting VA patients. I also serve as the Co-Director of the UCSF/SF-VAMC Skeletal Biology and Biomechanics Core to provide comprehensive skeletal phenotyping services to more than 50 VA, NIH, and DOD projects. During this RCS award period I will continue to: (1) Determine the therapeutic potential of the CaSR in treating osteoporosis and facilitating bone fracture repair and underlying mechanisms: We demonstrated previously an essential role of the CaSR in prenatal skeletal development and postnatal bone accrual by regulating parathyroid cell (PTC) functions and cell-autonomous activities in chondrocytes and osteoblasts. Based on those studies, we developed a new regimen to enhance the FDA-approved parathyroid hormone (PTH) therapy by targeting the CaSR in bone for osteoporosis without producing hypercalcemic side-effects. Promising results of our preclinical animal studies have led to a VA Merit Review proposal to initiate a clinical trial on VA patients with this new regimen. (2) Assess the role of CaSR in inducing neurodegeneration and its therapeutic potential to treat acute and chronic brain diseases: My lab was the first to uncover physical and functional interactions of CaSR with the type B γ-amino butyric acid (GABA) receptor type 1 (GABA-B-R1), which is a critical receptor producing inhibitory neurotransmission to prevent neuronal overactivity and subsequent cell death in the brain. Based on our recent findings that CaSR overexpression is closely associated with neuronal death in brains of mice subjected to ischemia (i.e., oxygen and nutrient deprivation) and mouse models of early- onset familial Alzheimer's Disease, we have begun to test the hypothesis that CaSR overexpression/overactivity critically promotes neuronal death and brain degeneration in those diseases by interfering with GABA-B-R1 signaling. Our comprehensive in vivo and in vitro experiments strongly support this concept. I will continue to pursue this line of research, aiming to provide strongest scientific bases to guide future clinical trials to treat multiple devastating brain diseases. (3) Determine the role of CaSR-associated signaling molecules in mediating parathyroid functions: My group studied different genetically manipulated mouse models to delineate CaSR-mediated signaling mechanisms in parathyroid gland (PTG), which is the major producer of PTH that critically controls mineral balance. We found that mice with CaSR deficiency in their PTGs (PTCCaSR+/- ) acquire hyperparathyroidism (HPT), a prevalent metabolic disease afflicting >1% of aging adults. Interestingly, in the bac...