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