BLR&D Research Career Scientist Award

BLR

• 批准号: 10515310
• 负责人: Wenhan Chang
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515310
• 关键词: Ablation; Acute; Adult; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Apoptosis; Apoptotic; Applications Grants; Automobile Driving; Award; Biochemical; Biology; Biomechanics; Bone Diseases; Brain; Brain Diseases; Butyric Acids; CCL4 gene; CXCL11 gene; CYP27B1 gene; Calcium-Sensing Receptors; Cardiovascular system; Cell Death; Cell physiology; Cells; Chondrocytes; Chronic; Clinical; Clinical Trials; Code; Combined Modality Therapy; Communities; Consultations; Coupled; Data; Development; Disease; Disease of parathyroid glands; Early Onset Familial Alzheimer' s Disease; Equilibrium; Excision; FDA approved; Financial Hardship; Fracture; Funding; Future; Genes; Healthcare Systems; Heterodimerization; Heterozygote; Homeostasis; Hormonal; Hormone secretion; Hypercalcemia; Hyperparathyroidism; IGF1 gene; IGF1R gene; In Vitro; Injections; International; Ischemia; Ischemic Brain Injury; Kidney Failure; Knockout Mice; Laboratories; LoxP-flanked allele; Lung; Malignant Neoplasms; Mammary gland; Manuscripts; Mediating; Mediator; Metabolic Diseases; Metabolism; Minerals; Modeling; Molecular; Molecular Structure; Mus; Nature; Nerve Degeneration; Neurons; Oklahoma; Organ; Osteoblasts; Osteoporosis; Oxygen; PTH gene; Parathyroid gland; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological; Play; Population; Preparation; Production; Property; Publications; Quality of life; Regimen; Research; Research Project Grants; Role; Scientist; Services; Signal Transduction; Signaling Molecule; Skeletal Development; Skin; Small Inducible Cytokine B11; System; Technology; Testing; Therapeutic; Time; Tissues; Translational Research; Traumatic Brain Injury; United States National Institutes of Health; Universities; Veterans; Vitamin D Deficiency; antagonist; anticancer research; base; bone; bone fracture repair; brain research; career; cellular imaging; experimental study; extracellular; gamma-Aminobutyric Acid; gastrointestinal; genetic approach; genetic manipulation; healing; hormone therapy; in vivo; mouse model; neuron loss; neuroprotection; neurotransmission; new combination therapies; novel; novel therapeutics; nutrient deprivation; overexpression; pharmacologic; postnatal; pre-clinical; prenatal; prevent; receptor; receptor-mediated signaling; side effect; skeletal; skeletal disorder; social; targeted treatment

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 background of PTCCaSR+/- mice, concurrent removal of GABA-B-R1 in PTGs prevents the development of HPT, suggesting that GABA-B-R1 is a critical mediator of PTH hypersecretion in those diseases. I will continue this line of research to determine if aberrant expression and/or activity of CaSR and GABA-B-R1 also play a fundamental role in causing PTH overproduction and subsequent mineral imbalance in lieu of Ca2+ and/or vitamin D deficiency or kidney failure. (4) Define actions of CaSR and FGF23 in other vital organs through collaborative research: We generated novel floxed-CaSR and floxed-FGF23 mice that permits assessments of tissue-specific actions of CaSR and FGF23, which is another critical factor mediating mineral and hormonal homeostasis in physiological and disease states. We have provided those mice as well as essential consultation and technical assistance to >20 local and international renown laboratories conducting skin, cardiovascular, gastrointestinal, pulmonary, mammary glands, brain, and cancer research. Our collaborative studies have revealed diverse actions of CaSR and FGF23 in those systems, as demonstrated in numerous high-impact publications.

我的研究领域包括信号转导、分子结构和肿瘤的病理生理作用