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：
8356515
负责人：
YUNCHAO SU
金额：
$ 7.5万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8356515
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. PUBLIC HEALTH RELEVANCE: We recently reported that global calpain knockout prevents pulmonary vascular remodeling in hypoxia- induced pulmonary hypertension and the calpain inhibitor MDL28170 prevents the progression of established pulmonary hypertension induced by monocrotaline. This proposal is to study a novel hypothesis that calpain activates intracellular TGF?1 in idiopathic pulmonary arterial hypertension. The contribution of the proposed research to the field of pulmonary hypertension is expected to be leading to development of new pharmacologic strategies that will target calpain in pulmonary vascular remodeling associated with pulmonary hypertension. Successful completion of this project will help provide a new method for the prevention and treatment of pulmonary hypertension.

描述（由申请人提供）：肺动脉高压（PAH）是一种严重而进行的进行性疾病，其关键特征是肺血管重塑，与细胞外基质的积累相关，包括胶原蛋白，包括胶原蛋白，包括血管细胞的增殖，内膜和内膜增厚，粘膜和复合物和复合物和状态，并导致摄影剂，并导致良好的固定剂，以供应到固定剂，以及以下方面的，肺动脉压的持续升高。 PDGF，EGF，VEGF和TGF？1参与肺血管重塑的过程。我们最近首次报道了钙蛋白酶的全球敲除可防止缺氧诱导的肺动脉高压的肺血管重塑，并阻止钙蛋白酶抑制剂MDL28170防止由单蛋白氨基氨酸氨酸氨酸氨酸酯引起的已建立肺动脉高压的进展。钙蛋白酶是钙依赖性的非溶酶体中性半胱氨酸内肽酶的家族，可通过有限的蛋白水解在包括肺血管细胞在内的哺乳动物细胞中起作用。 CALPAIN是PDGF，EGF和VEGF的下游信号转导分子，并介导PDGF-和EGF诱导的胶原蛋白合成以及肺动脉平滑肌细胞（PASMCS）的胶原蛋白合成以及VEGF诱导的肺部内皮细胞血管生成（PAMECS）的增殖。最近，我们发现钙蛋白酶切割并激活TGF？1，并且是一个内部的TGF？信号途径存在于PASMC中。为了验证钙蛋白酶在动物模型中的肺血管重塑中的作用，我们将利用肺动脉高压突破性倡议（PHBI）提供的人类肺组织（PHBI），并测试了我们的新假设，即钙蛋白酶激活了与IPAH相关的肺血管重建中的细胞内TGF？1。为了检验这一假设，我们提出了一种以下特定目的的多学科方法：＃1是确定钙蛋白酶抑制是否阻止或减弱来自特发性肺动脉高压（IPAH）的PASMC和PASCS和PAECS的胶原蛋白合成和PAMCS的增殖；＃2是确定钙蛋白酶在PASMC和IPAH患者的PAMC中是否激活细胞内TGF？1。 calpain在肺血管细胞中调节胶原蛋白合成和增殖的证明可能会导致新的药理学策略的发展，这些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。公共卫生相关性：我们最近报道，全球钙蛋白酶敲除可以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则阻止了由单蛋白氨基氨酸氨酸氨基氨酸引起的已建立肺高血压的进展。该建议是研究一种新的假设，该假说在特发性肺动脉高压中激活细胞内TGF？1。拟议的研究对肺动脉高压领域的贡献有望导致新的药理策略的发展，这些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。成功完成该项目将有助于提供一种新方法，以预防和治疗肺动脉高压。