EBP50 REGULATION OF PTH RECEPTOR IN BONE AND KIDNEY

EBP50 对骨和肾中 PTH 受体的调节

• 批准号: 7903700
• 负责人: Peter A Friedman
• 金额: $ 10.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903700
• 关键词: Adaptor Signaling Protein; Binding Proteins; Biochemical; Biological; Calcium; Cells; Data; Employee Strikes; Equilibrium; Exhibits; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Goals; Homeostasis; Kidney; Knowledge; Laboratories; Lead; Ligands; Link; Mediating; Molecular; Outcome; Parathyroid Hormone Receptor; Parathyroid Hormone Receptors; Parathyroid Hormones; Process; Proteins; RNA Splicing; Recycling; Regulation; Research; Research Personnel; Role; Signal Transduction; Techniques; Testing; Tissues; Work; bone; bone cell; calcium phosphate; desensitization; extracellular; ezrin; hormone resistance; human PTH protein; novel; programs; protein 50 kDa; receptor; response; trafficking

The long-term goal of this project is to elucidate the cellular mechanisms of parathyroid hormone receptor (PTH1R) action. The PTH1R regulates extracellular calcium and phosphate homeostasis by its actions on kidney and bone. Like other G protein-coupled receptors, the PTH1R exhibits a cyclical process of activation, desensitization, internalization, and resensitization. Receptor desensitization provides a mechanism to protect cells against excessive stimulation, while resensitization guards cells against prolonged inactivity and hormone resistance. Unlike most other receptors, however, the PTH1R exhibits considerable cell- and tissue-specific differences in its activation. These differences cannot be ascribed to alternatively spliced receptor forms, receptor abundance, or G protein availability. Recent evidence suggests that the cytoplasmic adaptor protein ezrin-binding protein 50 kD (EBP50) may contribute to cell-specific PTH1R signaling and internalization. The central goal of the proposed studies is to examine the interaction and modulatory activity of EBP50 on all aspects of PTH1R cycling. Four specific aims are developed to test the unifying hypothesis that EBP50 regulates ligand-specific responses of the PTH1R. Aim 1 will characterize the effects of EBP50 on cell-specific PTH1R activation. Aim 2 will describe EBP50 effects on PTH1R desensitization. Aim 3 will identify structural determinants of EBP50 that are involved in PTH1R internalization. Aim 4 will determine the effects of EBP50 on PTH1R recycling. The planned studies employ an array of cell biological, biochemical, and molecular biological techniques that will be applied to specific kidney and bone cells that are the primary targets of PTH action. Preliminary data provide provisional support and establish the feasibility for much of the proposed work. The planned studies will yield novel and important information on the mechanism and role by which the PTH1R regulates extracellular calcium homeostasis. The results will provide greater understanding of the initiation and termination of PTH1R action. The outcomes may suggest additional pathophysiological mechanisms causing PTH resistance and lead to new treatment opportunities.

该项目的长期目标是阐明甲状旁腺激素受体的细胞机制 (PTH1R) 行动。 PTH1R 通过其作用来调节细胞外钙和磷酸盐稳态 肾和骨。与其他 G 蛋白偶联受体一样，PTH1R 表现出一个循环过程： 激活、脱敏、内化和再敏化。受体脱敏提供了 保护细胞免受过度刺激的机制，而再敏化则保护细胞免受过度刺激 长期不活动和激素抵抗。然而，与大多数其他受体不同，PTH1R 表现出 其激活存在相当大的细胞和组织特异性差异。这些差异不能归因于 选择性剪接受体形式、受体丰度或 G 蛋白可用性。最近的证据表明 细胞质接头蛋白 ezrin 结合蛋白 50 kD (EBP50) 可能有助于细胞特异性 PTH1R 信号传导和内化。拟议研究的中心目标是检查相互作用 以及 EBP50 对 PTH1R 循环各方面的调节活性。制定了四个具体目标来测试 EBP50 调节 PTH1R 配体特异性反应的统一假设。目标1将 描述 EBP50 对细胞特异性 PTH1R 激活的影响。目标 2 将描述 EBP50 对 PTH1R 脱敏。目标 3 将确定参与 PTH1R 的 EBP50 的结构决定因素 内化。目标 4 将确定 EBP50 对 PTH1R 回收的影响。计划的研究采用 一系列细胞生物学、生化和分子生物学技术，将应用于特定的 肾细胞和骨细胞是 PTH 作用的主要目标。初步数据提供临时 支持大部分拟议工作并确定其可行性。计划中的研究将产生新颖且 有关 PTH1R 调节细胞外钙的机制和作用的重要信息 体内平衡。结果将有助于更好地了解 PTH1R 的启动和终止 行动。结果可能表明导致 PTH 耐药和的其他病理生理机制 带来新的治疗机会。