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.

项目总结 这项研究计划的根本目的是增进我们对发病机制的了解。 心脏纤维化症。我们最近发现了一例由框架引起的新的家族性纤维性心肌病 老年人纤溶酶原激活物抑制物-1[PAI-1]编码基因SERPINE1的突变 阿米什血缘关系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，心脏损伤的常见并发症和衰老的表现。我们之前已经 据报道，PAI-1基因完全缺陷的小鼠和人类经历了自发的年龄增长- 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(CMS)，部分解释了PAI-1缺陷小鼠发生广泛纤维化的原因 衰老期间的心肌病和心脏损伤。尽管幼年PAI-1缺陷小鼠的 心脏结构和功能，它们会出现明显的细胞外基质(ECM)失调， 心脏黏附受体、增强的促纤维化信号和强大的心肌激活 调节应激纤维化反应的转录网络。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因子 控制CM促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，以及3) 调节ECM引导的CM对应激的反应。这个应用程序由三个具体目标组成 旨在阐明PAI-1通过协调的方式对促纤维化信号的细胞特异性调节 重现人类罕见疾病的新型组织特异性基因敲除小鼠的研究 纤维性心肌病的队列，以及细胞外基质成分作用的机械性测定 关于心肌中的促纤维化信号。这项提案的首要目标是告知 通过广泛的途径确定防治心肌纤维化的新的治疗靶点 遗传性PAI-1缺乏的棱镜和随之而来的心脏ECM生物学失调。这个项目 利用多学科系统生物学方法了解环境与环境管理网络的功能 在心脏中随着年龄的增长和对压力的反应。我们将同时使用现有的和新的小鼠 年龄依赖性心肌纤维化模型以确定心脏细胞外基质在发病前的动态变化 并加速纤维化。我们将扩展我们的临床前模型的发现，用深度表型 因PAI-1完全缺乏而患家族性纤维性心肌病的独特人群。我们 将以我们对年龄依赖性心肌纤维化模型的观察为基础，通过批判性地检查 单个ECM底物调节小鼠和人类CMS的表观遗传和合成程序 并明确PAI-1缺乏如何增强心肌细胞-成纤维细胞-巨噬细胞的通讯 以增强心脏纤维化。