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Calpain Activates Intracellular TGF-beta1 in Pulmonary Hypertension

肺动脉高压中钙蛋白酶激活细胞内 TGF-β1

基本信息

批准号：
8516591
负责人：
YUNCHAO SU
金额：
$ 7.14万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516591
关键词：
Animal Model Attenuated Blood Vessels Calcium Calpain Caspase Categories Cell Proliferation Cells Cleaved cell Clinical Data Collagen Complex Cysteine Protease Development Disease EGF gene Exhibits Extracellular Matrix Family Functional disorder Human Hypertrophy Hypoxia Intervention Knock-out Lead Lesion Lung Mammalian Cell Medial Mediating Mediator of activation protein Methods Monocrotaline Outcome Patients Phosphorylation Platelet-Derived Growth Factor Prevention Process Progressive Disease Protein Isoforms Proteins Proteolysis Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Regulation Reporting Research Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Structure of parenchyma of lung TGF-beta type I receptor Testing Therapeutic Time Vascular Endothelial Growth Factors Vascular remodeling angiogenesis calpain inhibitor calpastatin human TGFB1 protein inhibitor/antagonist interdisciplinary approach neutralizing antibody novel pressure prevent pulmonary arterial hypertension pulmonary artery endothelial cell

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling that is associated with accumulation of extracellular matrix, including collagen, and vascular cell proliferation, medial and adventitial thickening, occlusive neointima, and complex plexiform lesions, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure. PDGF, EGF, VEGF, and TGF?1 participate in the process of pulmonary vascular remodeling. We recently reported for the first time that global knockout of calpain prevents pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension and that the calpain inhibitor MDL28170 prevents the progression of established pulmonary hypertension induced by monocrotaline. Calpain is a family of calcium-dependent non-lysosomal neutral cysteine endopeptidases that act via limited proteolysis of substrate proteins in mammalian cells including pulmonary vascular cells. Calpain is the downstream signal transduction molecule of PDGF, EGF and VEGF, and mediates PDGF- and EGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) and VEGF-induced angiogenesis of pulmonary artery endothelial cells (PAECs). We have recently found that calpain cleaves and activates TGF?1 and that an intracrine TGF? signal pathway exists in PASMCs. To validate the role of calpain in pulmonary vascular remodeling in animal models, we will take advantage of the human lung tissues provided by the Pulmonary Hypertension Breakthrough Initiative (PHBI) and test our novel hypothesis that calpain activates intracellular TGF?1 in pulmonary vascular remodeling associated with IPAH. To test this hypothesis, we propose a multidisciplinary approach focusing on the following specific aims: #1 is to determine whether calpain inhibition prevents or attenuates collagen synthesis and proliferation of PASMCs and PAECs from patients with idiopathic pulmonary arterial hypertension (IPAH); #2 is to determine whether calpain activates intracellular TGF?1 in PASMCs and PAECs from patients with IPAH. Proof of regulation of collagen synthesis and proliferation by calpain in pulmonary vascular cells may lead to development of new pharmacologic strategies that will target calpain in pulmonary vascular remodeling associated with pulmonary hypertension.

描述（申请人提供）：肺动脉高压（PAH）是一种严重的进行性疾病，其关键特征是肺血管重塑，与细胞外基质（包括胶原蛋白）的积累和血管细胞增殖、内膜和外膜增厚、闭塞性新内膜和复杂的丛状病变相关，导致毛细血管前肺动脉闭塞和肺动脉压持续升高。 PDGF、EGF、VEGF和TGF?1参与肺血管重塑过程。我们最近首次报道，钙蛋白酶的整体敲除可防止缺氧诱导的肺动脉高压中的肺血管重塑，而钙蛋白酶抑制剂 MDL28170 可防止野百合碱诱导的肺动脉高压的进展。钙蛋白酶是钙依赖性非溶酶体中性半胱氨酸内肽酶家族，通过对哺乳动物细胞（包括肺血管细胞）中的底物蛋白进行有限的蛋白水解来发挥作用。钙蛋白酶是PDGF、EGF和VEGF的下游信号转导分子，介导PDGF和EGF诱导的肺动脉平滑肌细胞(PASMC)的胶原合成和增殖以及VEGF诱导的肺动脉内皮细胞(PAEC)的血管生成。我们最近发现钙蛋白酶裂解并激活 TGF?1 以及内分泌的 TGF?1。 PASMCs 中存在信号通路。为了在动物模型中验证钙蛋白酶在肺血管重塑中的作用，我们将利用肺动脉高压突破计划（PHBI）提供的人类肺组织，并测试我们的新假设，即钙蛋白酶在与IPAH相关的肺血管重塑中激活细胞内TGF?1。为了检验这一假设，我们提出了一种多学科方法，重点关注以下具体目标：#1 是确定钙蛋白酶抑制是否会阻止或减弱特发性肺动脉高压 (IPAH) 患者的 PASMC 和 PAEC 的胶原蛋白合成和增殖； #2 是确定钙蛋白酶是否激活 IPAH 患者 PASMC 和 PAEC 中的细胞内 TGF?1。钙蛋白酶在肺血管细胞中调节胶原蛋白合成和增殖的证据可能会导致新的药理学策略的开发，该策略将针对与肺动脉高压相关的肺血管重塑中的钙蛋白酶。