BLR&D Research Career Scientist Award

我的研究调查了细胞的信号转导、分子结构和病理生理作用。 系统性红斑狼疮患者细胞外钙敏感受体及其相关信号分子的研究 矿物质和骨骼动态平衡，以及最近在诱发脑部疾病中的作用，并探索了 该受体治疗几种困扰VA患者的流行疾病的潜力。我还担任 UCSF/SF-VAMC骨骼生物学和生物力学核心联席主任提供全面的 为50多个退伍军人事务部、美国国立卫生研究院和国防部项目提供骨骼分型服务。在本次RCS颁奖期间，我将 继续：(1)确定CASR在治疗骨质疏松症和促进 骨折修复和潜在机制：我们以前证明了骨修复的一个重要作用 CaSR通过调节甲状旁腺细胞(PTC)在产前骨骼发育和出生后骨积累中的作用 软骨细胞和成骨细胞的功能和细胞自主活动。基于这些研究，我们 开发了一种新的方案来加强FDA批准的甲状旁腺激素(PTH)治疗，通过靶向 骨钙素缓释片用于骨质疏松症，不会产生高钙性副作用。我们取得了可喜的成果 临床前动物研究导致了一项VA优点审查提案，该提案旨在启动一项针对VA患者的临床试验 这种新的养生法。(2)评价CaSR在诱导神经变性中的作用及其治疗 治疗急性和慢性脑部疾病的潜力：我的实验室是第一个发现物理和功能的 钙结合蛋白受体与B型γ-氨基丁酸1型受体的相互作用 产生抑制神经传递以防止神经元过度活动和后续细胞的关键受体 大脑中的死亡。根据我们最近的发现，CaSR的过度表达与神经元密切相关 脑缺血(即缺氧和营养剥夺)小鼠的脑死亡和小鼠早期脑缺血模型 家族性阿尔茨海默病，我们已经开始检验CaSR过度表达/过度活动的假设 通过干扰GABA-B-R1在这些疾病中关键地促进神经元死亡和脑变性 发信号。我们全面的体内和体外实验有力地支持了这一概念。我会继续 继续这方面的研究，旨在为指导未来的临床试验治疗提供最有力的科学依据 多种毁灭性的脑部疾病。(3)确定CaSR相关信号分子在 调节甲状旁腺功能：我的团队研究了不同的基因操纵小鼠模型 阐明CaSR在甲状旁腺(PTG)中的信号机制，PTG是甲状旁腺的主要产生者 关键控制矿物质平衡的甲状旁腺素。我们发现CaSR缺乏的小鼠的PTG(PTCCaSR+/- 获得甲状旁腺机能亢进症(HPT)，这是一种普遍存在的代谢性疾病，困扰着1%的老年人。有趣的是， 在PTCCaSR+/-小鼠的背景下，PTG中GABA-B-R1的同时去除阻止了发育 提示GABA-B-R1在这些疾病中是甲状旁腺素高分泌的关键介质。这就做 继续这项研究，以确定CaSR和GABA-B-R1的异常表达和/或活性是否也 在导致甲状旁腺激素过度生产和随后的矿物质失衡中发挥基础性作用，而不是钙和/或 维生素D缺乏或肾功能衰竭。(4)明确CaSR和FGF23在其他重要器官中的作用 合作研究：我们培育了允许评估的新型FLOXED-CaSR和FLOXED-FGF23小鼠 CaSR和FGF23的组织特异性作用，这是另一个调节矿物质和激素的关键因素 生理和疾病状态下的动态平衡。我们已经为这些老鼠提供了必要的咨询服务 并为20家当地和国际知名实验室提供技术援助，这些实验室从事皮肤、心血管、 胃肠、肺、乳腺、脑和癌症研究。我们的合作研究已经 揭示了CaSR和FGF23在这些系统中的不同行为，如许多高影响 出版物。

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.