BLRD Research Career Scientist Award Application

Veterans Affairs Med Ctr San Francisco, San Francisco CA

Investigators

Linked publications, trials & patents

Abstract

My research investigates signal transduction, molecular structures, and pathophysiological actions of the extracellular calcium-sensing receptor (CaSR) and its associated signaling molecules in the regulation of mineral and skeletal homeostasis and more recently in the induction of brain diseases. During the current research Career Scientist (RCS) award period, we uncovered the molecular actions of the CaSR in regulating skeletal, parathyroid, and neuronal functions in both physiological and pathological contexts. During the next RCS award period, my research will leverage those CaSR actions to explore the pharmaceutical potentials of the receptor for treatments of the following aging-related diseases. (i) Osteoporosis and bone fracture. We demonstrated previously the critical roles of the CaSR in prenatal skeletal development and postnatal bone accrual by regulating parathyroid cell (PTC) functions and cell-autonomous activities of chondrocytes and osteoblasts. Based on those studies, we developed a new regimen to enhance the FDA-approved parathyroid hormone (PTH) therapy by co-targeting the CaSR in bone to treat osteoporosis without hypercalcemic side- effects. Promising results from preclinical animal studies had led to a VA Merit Review award for a clinical trial on VA patients with this new regimen. (ii) Neurodegeneration and dementia. My lab uncovered physical and functional interactions of CaSR with the type B γ-amino butyric acid (GABA) receptor type 1 (GABA-B-R1), which critically mediates inhibitory neurotransmission to prevent neuronal overactivity and subsequent neurodegeneration. 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) or traumatic brain injuries, 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. This hypothesis is provisionally supported by our comprehensive in vivo and in vitro pilot experiments. We will continue to pursue this line of research, aiming to develop pharmaceutical regimens to treat neurodegeneration due to aging and other brain injuries. (iii) Primary hyperparathyroidism (HPT). My group studied different genetically manipulated mouse models to delineate signaling mechanisms mediating parathyroid cell functions, particularly the secretion of parathyroid hormone (PTH). We found that mice with CaSR deficiency in their PTCs (PTCCaSR+/-) acquire HPT. Interestingly, in the background of PTCCaSR+/- mice, concurrent removal of GABA-B-R1 or amyloid precursor protein (APP) in the same PTCs prevents the development of HPT. We further found that Ab1-42, a cleaved product of APP, profoundly stimulates PTH section, potentially by binding and activating CaSR/GABA-B-R1 heterodimer, indicating Ab1-42/GABA-B- R1/CaSR signaling as a critical driver of PTH hypersecretion in primary HPT. I will continue this line of research and test pharmacological regimens targeting CaSR/GABA-B-R1 heterodimer and reducing Ab1-42 access to treat the disease. In addition to the above research activities, I will continue to serve as the Director of the UCSF/SF-VAMC Skeletal Biology and Biomechanics Core to provide comprehensive skeletal phenotyping services to more than 75 VA, NIH, and DOD projects and adopt the state-of-the-art technologies to enhance multidisciplinary research in the SFVMAC and the greater UCSF community. This Core has been designated by a new BLRD/CSRD FRACTURE CURB Collaborative Merit Review program to provide histomorphology and molecular biology services to 8 Merit Review projects in 7 VA sites nationwide. I will also continue to disseminate the floxed-CaSR and floxed-FGF23 mice that we generated and provide necessary reagents and intellectual support to collaborators around the world to delineate tissue-specific actions of CaSR and FGF23 in skin, cardiovascular, gastrointestinal, pulmonary, mammary glands, brain, immune system, and/or cancer research, as our prior collaborative studies have uncovered diverse actions of CaSR and FGF23 in each of those systems.