Spontaneous cardiac fibrosis in PAI-1-deficient mice and men: A rare mutation informs a common molecular pathophysiology

PAI-1 缺陷小鼠和男性的自发性心脏纤维化：一种罕见的突变揭示了一种常见的分子病理生理学

基本信息

批准号：
9908161
负责人：
Douglas E Vaughan
金额：
$ 67.14万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY The fundamental objective of this research program is to advance our understanding of the pathogenesis of cardiac fibrosis. Our recent identification of a novel familial fibrotic cardiomyopathy caused by a frame shift mutation in SERPINE1 (the gene that codes for plasminogen activator inhibitor-1 [PAI-1]) in an Old Order Amish kindred provides an exceptional opportunity to define the molecular pathophysiology of cardiac fibrosis, a common complication of cardiac injury and manifestation of aging. We have previously reported that mice and humans with complete genetic deficiency of PAI-1 undergo spontaneous age- dependent cardiac selective fibrosis. We have also determined that PAI-1 regulates profibrotic signals by cardiomyocytes (CMs), partially explaining why PAI-1-deficient mice undergo extensive fibrotic cardiomyopathy during aging and cardiac injury. Although young PAI-1 deficient mice have normal cardiac structure and function, they develop marked extracellular matrix (ECM) dysregulation, changes in cardiac adhesion receptors, enhanced profibrotic signaling, and robust activation of myocardial transcriptional networks that mediate the fibrotic response to stress. Based on these findings, we hypothesize that PAI-1 serves as a pivotal regulator of cardiac fibrosis in mice and humans by 1) controlling CM profibrotic cytokine generation, 2) regulating monocytic responses to cardiac injury, and 3) modulating ECM-directed CM responses to stress. This application is composed of three specific Aims designed to elucidate the cell-specific regulation of profibrotic signaling by PAI-1, via coordinated investigation of novel tissue specific knockout mice that recapitulate the human disorder, a rare human cohort with fibrotic cardiomyopathy, and a mechanistic determination of the effects of ECM components on profibrotic signaling in the myocardium. The overarching goal for this proposal is to inform the identification of novel therapeutic targets for prevention and treatment of cardiac fibrosis broadly through the prism of genetic PAI-1 deficiency and the dysregulated cardiac ECM biology that follows. This project utilizes a multi-disciplinary systems biology approach to understanding the function of the ECM networks in the heart with aging and in response to stressors. We will use both established and new murine models of age-dependent cardiac fibrosis to define the dynamic changes in cardiac ECM that precede and precipitate fibrosis. We will extend the findings from our preclinical models with deep phenotyping of a unique cohort of humans with a familial fibrotic cardiomyopathy due to complete PAI-1 deficiency. We will build upon our observations from age-dependent cardiac fibrosis models by critically examining how individual ECM substrates regulate the epigenetic and synthetic programs of mouse and human CMs during injury and define how PAI-1 deficiency augments myocyte-fibroblast-macrophage communication to enhance cardiac fibrosis.

项目概要该研究计划的基本目标是增进我们对发病机制的了解心脏纤维化。我们最近发现了一种由框架引起的新型家族性纤维化心肌病旧基因中 SERPINE1（编码纤溶酶原激活剂抑制剂-1 [PAI-1] 的基因）的移位突变阿米什教派提供了一个特殊的机会来定义分子病理生理学心脏纤维化是心脏损伤的常见并发症，也是衰老的表现。我们之前有过报道称，具有 PAI-1 完全遗传缺陷的小鼠和人类会经历自发的衰老过程。依赖性心脏选择性纤维化。我们还确定 PAI-1 通过以下方式调节促纤维化信号：心肌细胞 (CM)，部分解释了为什么 PAI-1 缺陷小鼠会发生广泛的纤维化衰老和心脏损伤期间的心肌病。尽管年轻的 PAI-1 缺陷小鼠具有正常的心脏结构和功能，它们会出现明显的细胞外基质（ECM）失调，心脏粘附受体、增强的促纤维化信号传导以及心肌的强烈激活介导应激纤维化反应的转录网络。基于这些发现，我们假设 PAI-1 作为小鼠和人类心脏纤维化的关键调节因子 1) 控制 CM 促纤维化细胞因子的生成，2) 调节单核细胞对心脏损伤的反应，以及 3) 调节 ECM 引导的 CM 对压力的反应。该应用程序由三个具体目标组成旨在阐明 PAI-1 对促纤维化信号传导的细胞特异性调节，通过协调研究重现人类疾病（一种罕见的人类疾病）的新型组织特异性基因敲除小鼠纤维化心肌病队列，以及 ECM 成分作用的机制确定关于心肌中的促纤维化信号传导。该提案的总体目标是告知通过广泛地确定预防和治疗心脏纤维化的新治疗靶点遗传性 PAI-1 缺陷和随之而来的心脏 ECM 生物学失调。这个项目利用多学科系统生物学方法来了解 ECM 网络的功能心脏随着衰老和对压力的反应。我们将使用现有的和新的小鼠年龄依赖性心脏纤维化模型来定义心脏 ECM 的动态变化并加速纤维化。我们将通过深度表型分析来扩展我们的临床前模型的发现一群因完全缺乏 PAI-1 而患有家族性纤维化心肌病的独特人群。我们将基于我们对年龄依赖性心脏纤维化模型的观察，批判性地研究如何个体 ECM 底物调节小鼠和人类 CM 的表观遗传和合成程序损伤期间并确定 PAI-1 缺陷如何增强肌细胞 - 成纤维细胞 - 巨噬细胞通讯以增强心脏纤维化。