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
- 来源:
- 关键词:AgeAgingAmishAngiotensin IIAttenuatedBiologyBone MarrowCardiacCardiac MyocytesCardiac developmentCardiomyopathiesCardiovascular DiseasesCardiovascular systemCellsCicatrixClinicalCoculture TechniquesCodeCollagenCommunicationComplicationDNA MethylationDNA methylation profilingDiseaseElementsEpigenetic ProcessExhibitsExtracellular MatrixFibroblastsFibronectinsFibrosisFrameshift MutationFunctional disorderGene Expression ProfileGenerationsGeneticGenetic TranscriptionGoalsHealthcareHeartHeart DiseasesHeart InjuriesHeart TransplantationHeart failureHeterozygoteHomeostasisHumanIndividualInflammatoryInfusion proceduresInjuryInvestigationKnock-outKnockout MiceLamininMediatingModelingMolecularMolecular ProfilingMononuclearMusMuscle CellsMutationMyocardialMyocardiumPathogenesisPathway interactionsPatientsPhenotypePlasminogen Activator Inhibitor 1PopulationPre-Clinical ModelPreventionProcessProfibrotic signalProteinsRegulationReportingResearchRoleSERPINE1 geneSignal TransductionStressStructureSystems BiologyTestingTherapeuticTissuesTransforming Growth FactorsTransplantationadhesion receptorage relatedbasecohortcoronary fibrosisdesigneffective therapyfibrogenesishuman diseaseinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocyteskindredmacrophagemenmonocytemouse modelmultidisciplinarynew therapeutic targetnovelprofibrotic cytokineprogramsresponseresponse to injurysenescencestressortooltranscriptometranscriptome sequencing
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
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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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