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:
    10402774
  • 负责人:
  • 金额:
    $ 67.08万
  • 依托单位:
  • 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 2023-12-31
  • 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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
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Douglas E Vaughan其他文献

1007-182 Aldosterone and plasma renin activity influence plasma plasminogen activato inhibitor-1 levels in overweight subjects
  • DOI:
    10.1016/s0735-1097(04)91875-x
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    James A.S Muldowney;Barbara C Roberts;Joseph W Covington;John A Schoenhard;Nancy J Brown;Douglas E Vaughan
  • 通讯作者:
    Douglas E Vaughan
1064-181 Distinct signaling pathways mediate protease activated receptor-dependent endothelial exocytosis
  • DOI:
    10.1016/s0735-1097(04)91968-7
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    John H Cleator;Douglas E Vaughan;Heidi E Hamm
  • 通讯作者:
    Heidi E Hamm

Douglas E Vaughan的其他文献

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{{ truncateString('Douglas E Vaughan', 18)}}的其他基金

Evolutionary Advantage of Heterozygous PAI-1 Deficiency in Humans
人类杂合 PAI-1 缺陷的进化优势
  • 批准号:
    10686583
  • 财政年份:
    2022
  • 资助金额:
    $ 67.08万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 67.08万
  • 项目类别:
Cardiovascular Regenerative Medicine
心血管再生医学
  • 批准号:
    8661256
  • 财政年份:
    2011
  • 资助金额:
    $ 67.08万
  • 项目类别:
Cardiovascular Regenerative Medicine
心血管再生医学
  • 批准号:
    8663728
  • 财政年份:
    2011
  • 资助金额:
    $ 67.08万
  • 项目类别:
Cardiovascular Regenerative Medicine
心血管再生医学
  • 批准号:
    8464219
  • 财政年份:
    2011
  • 资助金额:
    $ 67.08万
  • 项目类别:
Cardiovascular Regenerative Medicine
心血管再生医学
  • 批准号:
    8329605
  • 财政年份:
    2011
  • 资助金额:
    $ 67.08万
  • 项目类别:
CARDIOVASCULAR CORE
心血管核心
  • 批准号:
    7638639
  • 财政年份:
    2008
  • 资助金额:
    $ 67.08万
  • 项目类别:
Cell Therapy for Improving Cardiac Function
改善心脏功能的细胞疗法
  • 批准号:
    7212901
  • 财政年份:
    2007
  • 资助金额:
    $ 67.08万
  • 项目类别:
CARDIOVASCULAR CORE
心血管核心
  • 批准号:
    7560713
  • 财政年份:
    2007
  • 资助金额:
    $ 67.08万
  • 项目类别:
DEFINING STRATEGIES FOR IMPROVING ENDOTHELIAL/FIBRINOLYTIC DYFUNCTION IN OBESITY
制定改善肥胖症内皮/纤溶功能障碍的策略
  • 批准号:
    7605664
  • 财政年份:
    2006
  • 资助金额:
    $ 67.08万
  • 项目类别:

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