DIRECT CALPAIN-PTH1R BINDING AFFECTS ACTION OF PTH/PTHrP

CALPAIN-PTH1R 直接结合影响 PTH/PTHrP 的作用

• 批准号: 6960372
• 负责人: MASAKO SHIMADA
• 金额: $ 32.12万
• 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/6960372
• 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与脚手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的作用的关键。 PTH和PTHRP（PTH1R）的受体属于G蛋白偶联受体（GPCR）。 PTH的作用主要是通过直接对骨骼和肾脏作用来维持钙稳态。 PTHRP是细胞生长和分化的旁分泌调节剂，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有关。因此，通过PTH和PTHRP研究PTH1R的信号传导和生理功能对于理解疾病机制和发展新疗法至关重要。主要的研究目的是研究钙蛋白酶小亚基（28-kDa亚基）的作用，这是一种新型的相互作用，与甲状旁腺激素1受体（PTH1R）结合在PTH和/或PTHRP介导的信号传导和动作上。特定的目标1定义了钙蛋白酶介导的PTH1R裂解及其在PTH介导的细胞内事件中的作用。具体目标2研究了钙蛋白酶作为PTH引诱的下游过程的调节剂的作用。特定的目标3表征了小鼠在体内capn4的成骨细胞特异性缺失和从这些小鼠中分离出的CAPN4-NULL骨骨的表型。