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

• 批准号: 10402774
• 负责人: Douglas E Vaughan
• 金额: $ 67.08万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402774
• 关键词: Age; Aging; Amish; Angiotensin II; Attenuated; Biology; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cells; Cicatrix; Clinical; Coculture Techniques; Code; Collagen; Communication; Complication; DNA Methylation; DNA methylation profiling; Disease; Elements; Epigenetic Process; Exhibits; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Frameshift Mutation; Functional disorder; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Goals; Healthcare; Heart; Heart Diseases; Heart Injuries; Heart Transplantation; Heart failure; Heterozygote; Homeostasis; Human; Individual; Inflammatory; Infusion procedures; Injury; Investigation; Knock-out; Knockout Mice; Laminin; Mediating; Modeling; Molecular; Molecular Profiling; Mononuclear; Mus; Muscle Cells; Mutation; Myocardial; Myocardium; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasminogen Activator Inhibitor 1; Population; Pre-Clinical Model; Prevention; Process; Profibrotic signal; Proteins; Regulation; Reporting; Research; Role; SERPINE1 gene; Signal Transduction; Stress; Structure; Systems Biology; Testing; Therapeutic; Tissues; Transforming Growth Factors; Transplantation; adhesion receptor; age related; base; cohort; coronary fibrosis; design; effective therapy; fibrogenesis; human disease; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; kindred; macrophage; men; monocyte; mouse model; multidisciplinary; new therapeutic target; novel; profibrotic cytokine; programs; response; response to injury; senescence; stressor; tool; transcriptome; transcriptome sequencing

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.

项目摘要 该研究计划的基本目标是提高我们对发病机理的理解 心脏纤维化。我们最近确定了由框架引起的新型家族性纤维化心肌病 serpine1中的偏移突变（代码质激活剂抑制剂1 [PAI-1]的基因） Amish Kindred为定义的分子病理生理提供了一个非凡的机会 心脏纤维化，心脏损伤的常见并发症和衰老的表现。我们以前有 报道说，PAI-1完全遗传缺乏的小鼠和人类会经历自发年龄 依赖性心脏选择性纤维化。我们还确定PAI-1通过 心肌细胞（CMS），部分解释了为什么PAI-1缺陷小鼠会经历广泛的纤维化 衰老和心脏损伤期间的心肌病。虽然年轻的PAI-1不足小鼠正常 他们的心脏结构和功能，会产生明显的细胞外基质（ECM）失调，变化 心脏粘附受体，增强的纤维化信号传导和心肌的鲁棒激活 转录网络介导对应力的纤维化反应。基于这些发现，我们 假设PAI-1是小鼠和人类心脏纤维化的关键调节剂1） 控制CM纤维化细胞因子的产生，2）调节单核细胞对心脏损伤的反应，3） 调节ECM指导的CM对压力的响应。该应用由三个特定目标组成 旨在通过协调阐明PAI-1对纤维化信号传导的细胞特异性调节 研究新的组织特异性敲除小鼠，概括了人类疾病，这是一种罕见的人类 与纤维化心肌病的队列，以及对ECM成分效应的机械确定 在心肌中的纤维化信号传导上。该提议的总体目标是通知 通过广泛地鉴定预防和治疗心脏纤维化的新型治疗靶标 遗传PAI-1缺乏症的棱镜和随后的心脏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 在衰老的心脏中，应对压力源。我们将使用建立和新鼠 依赖年龄的心脏纤维化模型，以定义先前的心脏ECM的动态变化 并沉淀纤维化。我们将通过深层表型从我们的临床前模型中扩展发现 由于完全的PAI-1缺乏，独特的人类具有家族性纤维化心肌病。我们 通过批判性研究如何从依赖年龄的心脏纤维化模型观察到的基于我们的观察结果 单个ECM底物调节小鼠和人CM的表观遗传和合成程序 在受伤期间并定义PAI-1缺乏症如何增强心肌细胞 - 纤维细胞巨噬细胞通信 增强心脏纤维化。