DIREECT CALPAIN-PTH1R BINDING AFFECTS ACTIONS OF PTH/PTHrP

CALPAIN-PTH1R 直接结合影响 PTH/PTHrP 的作用

• 批准号: 7097253
• 负责人: MASAKO SHIMADA
• 金额: $ 31.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097253
• 关键词: animal genetic material tag; apoptosis; biological signal transduction; calpain; cell line; cell morphology; cell proliferation; cell surface receptors; chemical cleavage; hormone regulation /control mechanism; immunoprecipitation; laboratory mouse; osteoblasts; parathyroid hormone related protein; parathyroid hormones; phenotype; protein binding; protein structure function; receptor expression

DESCRIPTION (provided by applicant): The PTH1R binding to scaffolding proteins is key to the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in a cell- and membrane-specific manner. A receptor for PTH and PTHrP (PTH1R) belongs to G-protein coupling receptors (GPCR). PTH functions primarily to maintain calcium homeostasis through direct action on bone and kidney. PTHrP is a paracrine regulator of cellular growth and differentiation, and its ectopic expression in tumor cells is associated with bone metastasis and hypercalcemia in malignancy. Thus, to study signaling and physiological function of PTH1R via PTH and PTHrP is essential for understanding of mechanisms of diseases and developing novel therapy. The primary research goal is to investigate the role of calpain small subunits (the 28-kDa subunit), a novel interactor, binding to the parathyroid hormone 1 receptor (PTH1R) on PTH and/or PTHrP-mediated signaling and actions. Specific Aim 1 defines calpain-mediated cleavage of the PTH1R and its role on PTH-mediated intracellular events. Specific Aim 2 examines the role of calpain as a modulator of PTH-elicited downstream processes. Specific Aim 3 characterizes the phenotype of mice with osteoblast-specific deletion of Capn4 in vivo and of Capn4-null osteoblsts isolated from these mice.

描述（由申请人提供）：PTH1R 与支架蛋白的结合是甲状旁腺激素（PTH）和 PTH 相关肽（PTHrP）以细胞和膜特异性方式发挥作用的关键。 PTH 和 PTHrP 的受体 (PTH1R) 属于 G 蛋白偶联受体 (GPCR)。 PTH 的主要功能是通过直接作用于骨骼和肾脏来维持钙稳态。 PTHrP 是细胞生长和分化的旁分泌调节因子，其在肿瘤细胞中的异位表达与恶性肿瘤中的骨转移和高钙血症相关。因此，通过 PTH 和 PTHrP 研究 PTH1R 的信号传导和生理功能对于了解疾病机制和开发新疗法至关重要。主要研究目标是研究钙蛋白酶小亚基（28 kDa 亚基）（一种新型相互作用因子）与甲状旁腺激素 1 受体 (PTH1R) 结合对 PTH 和/或 PTHrP 介导的信号传导和作用的作用。具体目标 1 定义了钙蛋白酶介导的 PTH1R 裂解及其对 PTH 介导的细胞内事件的作用。具体目标 2 检查钙蛋白酶作为 PTH 引发的下游过程调节剂的作用。具体目标 3 描述了体内 Capn4 成骨细胞特异性缺失的小鼠以及从这些小鼠中分离出的 Capn4 缺失成骨细胞的表型。