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: 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
• 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
• 来源: https://reporter.nih.gov/project-details/9908161
• 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; 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; 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; cytokine; design; effective therapy; fibrogenesis; human disease; induced pluripotent stem cell; kindred; macrophage; men; monocyte; mouse model; multidisciplinary; new therapeutic target; novel; 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 这项研究计划的基本目标是促进我们对发病机制的理解 心脏纤维化我们最近鉴定了一种由框架引起的新型家族性纤维化心肌病 老年人中SERPINE 1（编码纤溶酶原激活物抑制剂-1 [派-1]的基因）的移位突变 订单阿米什亲属提供了一个特殊的机会，以确定分子病理生理学， 心脏纤维化是心脏损伤的常见并发症，也是衰老的表现。我们先前已经 报道，派-1基因完全缺失的小鼠和人类经历自发衰老， 心脏选择性纤维化我们还确定派-1通过以下方式调节促纤维化信号 心肌细胞（CM），部分解释了为什么派-1缺陷小鼠发生广泛的纤维化 老年心肌病和心脏损伤。尽管年轻派-1缺陷小鼠具有正常的 心脏结构和功能，他们发展明显的细胞外基质（ECM）失调， 心脏粘附受体，增强的促纤维化信号传导和心肌细胞的稳健激活 转录网络介导的纤维化反应的压力。基于这些发现，我们 假设派-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，和3） 调节ECM引导的CM对应激的反应。本申请由三个具体目标组成 旨在阐明派-1通过协调的细胞特异性调节促纤维化信号传导， 新的组织特异性敲除小鼠的研究重现了人类疾病，一种罕见的人类 纤维化心肌病队列，以及ECM成分作用的机制测定 对心肌纤维化信号的影响。本提案的总体目标是向 通过以下方法鉴定用于预防和治疗心脏纤维化的新的治疗靶点： 遗传派-1缺陷的棱镜和随之而来的失调的心脏ECM生物学。这个项目 利用多学科系统生物学方法来理解ECM网络的功能 随着年龄的增长和对压力的反应。我们将使用既有和新的小鼠 年龄依赖性心脏纤维化模型，以确定心脏ECM的动态变化， 并促进纤维化。我们将从我们的临床前模型中扩展研究结果， 一个独特的队列的人与家族性纤维化心肌病由于完全派-1缺乏症。我们 将建立在我们对年龄依赖性心脏纤维化模型的观察基础上， 单个ECM底物调节小鼠和人类CM的表观遗传和合成程序 并确定派-1缺陷如何增强肌细胞-成纤维细胞-巨噬细胞通讯 增强心脏纤维化