BLR&D Research Career Scientist Award

BLR

• 批准号: 10293574
• 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/10293574
• 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; CXCL11 gene; CYP27B1 gene; Calcium-Sensing Receptors; Cardiovascular system; Cell Death; Cell physiology; Cells; Chondrocytes; Chronic; Clinical; Clinical Trials; Code; 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; GABA Receptor; Genes; Healthcare Systems; Heterodimerization; Homeostasis; Hormonal; Hormone secretion; Hyperparathyroidism; IGF1 gene; IGF1R gene; In Vitro; Injections; International; Ischemia; Ischemic Brain Injury; Kidney Failure; Knockout Mice; Laboratories; Lead; LoxP-flanked allele; Lung; Malignant Neoplasms; Mammary gland; Manuscripts; Mediating; Mediator of activation protein; Metabolic Diseases; Metabolism; Minerals; Modeling; Molecular; Molecular Structure; Mus; Nature; Nerve Degeneration; Neurons; Oklahoma; Organ; Osteoblasts; Osteoporosis; Oxygen; PTH gene; Parathyroid gland; Pathologic; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Play; Population; Preparation; Property; Publications; Quality of life; Regimen; Research; Research Project Grants; Role; Scientist; Services; Signal Transduction; Signaling Molecule; Skeletal Development; Skin; 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; neurotransmission; novel; novel therapeutics; nutrient deprivation; overexpression; 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.

我的研究调查了信号转导、分子结构和病理生理作用 细胞外钙敏感受体（CaSR）及其相关信号分子在控制全身性 矿物质和骨骼稳态，以及最近在诱发脑部疾病方面的作用，并探索了 该受体治疗 VA 患者的几种常见疾病的治疗潜力。我也担任 UCSF/SF-VAMC 骨骼生物学和生物力学核心联合主任提供全面的 为 50 多个 VA、NIH 和 DOD 项目提供骨骼表型分析服务。在 RCS 奖励期间我将 继续：（1）确定CaSR在治疗骨质疏松症和促进骨质疏松症方面的治疗潜力 骨折修复和潜在机制：我们之前证明了骨折的重要作用 CaSR 通过调节甲状旁腺细胞 (PTC) 参与产前骨骼发育和产后骨生成 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 开发了一种新方案，通过针对以下部位来增强 FDA 批准的甲状旁腺激素（PTH）治疗 骨骼中的 CaSR 可治疗骨质疏松症，且不会产生高钙血症副作用。我们的成果令人鼓舞 临床前动物研究已导致 VA 优点审查提案启动对 VA 患者进行临床试验 这个新疗法。 (2) 评估CaSR在诱导神经退行性变中的作用及其治疗作用 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身体和功能性疾病的实验室 CaSR 与 B 型 γ-氨基丁酸 (GABA) 受体 1 型 (GABA-B-R1) 的相互作用，这是一种 产生抑制性神经传递的关键受体，以防止神经元过度活动和后续细胞 大脑中的死亡。根据我们最近的发现，CaSR 过度表达与神经元密切相关 遭受缺血（即缺氧和营养缺乏）的小鼠脑部死亡以及早期缺血性脑损伤的小鼠模型 发病家族性阿尔茨海默病，我们已经开始检验 CaSR 过度表达/过度活跃的假设 通过干扰 GABA-B-R1 严重促进这些疾病中的神经元死亡和脑退化 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 从事这一领域的研究，旨在提供最有力的科学基础来指导未来的临床试验 多种毁灭性脑部疾病。 (3)确定CaSR相关信号分子在 介导甲状旁腺功能：我的小组研究了不同的基因操纵小鼠模型 描述甲状旁腺 (PTG) 中 CaSR 介导的信号传导机制，甲状旁腺是甲状旁腺的主要产生者 PTH 关键控制矿物质平衡。我们发现，PTG 中存在 CaSR 缺陷的小鼠 (PTCCaSR+/- ）获得甲状旁腺功能亢进症 (HPT)，这是一种常见的代谢性疾病，困扰着 >1% 的老年人。有趣的是， 在 PTCCaSR+/- 小鼠的背景下，同时去除 PTG 中的 GABA-B-R1 会阻止发育 HPT 的相关性，表明 GABA-B-R1 是这些疾病中 PTH 分泌过多的关键介质。我会 继续这方面的研究以确定 CaSR 和 GABA-B-R1 的异常表达和/或活性是否也存在 在导致 PTH 过量产生和随后取代 Ca2+ 和/或的矿物质失衡中发挥重要作用 维生素 D 缺乏或肾衰竭。 (4) 通过定义CaSR和FGF23在其他重要器官中的作用 合作研究：我们培育了新型 floxed-CaSR 和 floxed-FGF23 小鼠，可以进行评估 CaSR 和 FGF23 的组织特异性作用，这是介导矿物质和激素的另一个关键因素 生理和疾病状态下的稳态。我们已经提供了这些老鼠以及必要的咨询 并为超过 20 个本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、 胃肠道、肺、乳腺、脑和癌症研究。我们的合作研究有 揭示了 CaSR 和 FGF23 在这些系统中的多种作用，正如许多高影响力中所证明的那样 出版物。