Dissecting the role of the cardiac fibroblast in hypertrophy.

剖析心脏成纤维细胞在肥厚中的作用。

基本信息

批准号：
10667595
负责人：
Jeffery D Molkentin
金额：
$ 60.9万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-18 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667595
关键词：
Actins Acute Adhesions Adult Biology Cardiac Cardiac Myocytes Cells Characteristics Collagen Collagen Fibril Collagen Type I Communication Complementary DNA Complex Data Defect Disease Dystroglycan Extracellular Matrix F-Actin Fibroblasts Fibrosis Focal Adhesions Foundations Future Gene Deletion Generations Genetic Growth Hand Heart Heart Diseases Heart Hypertrophy Heart failure Hydrogels Hypertrophy Impairment Injury Integrins Mediating Molecular Mus Muscle Cells Myocardial Infarction Myofibroblast Organ Pathogenesis Pathologic Pathway interactions Patients Play Process Production Property Protein-Lysine 6-Oxidase Receptors, Adrenergic, beta-1 Reporter Role Signal Pathway Signal Transduction Tamoxifen Testing Transforming Growth Factor beta Receptors Transgenic Mice Ventricular Remodeling beta Actin beta catenin cardiogenesis cell type coronary fibrosis crosslink density gamma Actin genomic locus healing heart function in vivo mouse model novel novel therapeutics overexpression paracrine periostin pressure protein aggregation response therapeutic target three dimensional cell culture tool

Actins Acute Adhesions Adult Biology Cardiac Cardiac Myocytes Cells Characteristics Collagen Collagen Fibril Collagen Type I Communication Complementary DNA Complex Data Defect Disease Dystroglycan Extracellular Matrix F-Actin Fibroblasts Fibrosis Focal Adhesions Foundations Future Gene Deletion Generations Genetic Growth Hand Heart Heart Diseases Heart Hypertrophy Heart failure Hydrogels Hypertrophy Impairment Injury Integrins Mediating Molecular Mus Muscle Cells Myocardial Infarction Myofibroblast Organ Pathogenesis Pathologic Pathway interactions Patients Play Process Production Property Protein-Lysine 6-Oxidase Receptors, Adrenergic, beta-1 Reporter Role Signal Pathway Signal Transduction Tamoxifen Testing Transforming Growth Factor beta Receptors Transgenic Mice Ventricular Remodeling beta Actin beta catenin cardiogenesis cell type coronary fibrosis crosslink density gamma Actin genomic locus healing heart function in vivo mouse model novel novel therapeutics overexpression paracrine periostin pressure protein aggregation response therapeutic target three dimensional cell culture tool

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项目摘要

Abstract The cardiac myocyte has long been the primary focus of studies attempting to elucidate the regulatory aspects underlying cardiac development and disease. However, recently the involvement of nonmyocytes has emerged as potentially just as important as myocytes in contributing to and controlling cardiac remodeling during progressive pathogenesis associated with heart failure. More specifically, the cardiac fibroblast and its ability to convert to myofibroblasts in promoting extracellular matrix (ECM) production, ventricular remodeling and the fibrotic response is now viewed as an equally critical regulator of cardiac biology. Here we will address how fibroblasts in the heart function as key determinants of disease and pathologic remodeling. We have developed important genetic tools that specifically target the fibroblast in the heart so that we can manipulate the activity of these cells. Thus, here we can now test the novel hypothesis that activated fibroblasts (myofibroblasts) are critical regulators of cardiac disease processes, not only involving fibrosis but also the ability of cardiomyocytes in the heart to properly hypertrophy. We will test the more specific hypothesis that fibroblasts regulate the density and integrity of the cardiac ECM and collagen that cardiomyocytes must sense as increased structural support in order to effectively hypertrophy in vivo. Indeed, we further hypothesize that the tension sensing mechanism within the cardiomyocyte extends outward to the ECM and its integrity or stiffness. This application has 3 specific aims: 1) To increase the structural rigor of collagen in the heart to investigate the impact on cardiomyocyte hypertrophic growth potential in vivo, 2) To genetically impair type I collagen formation in the heart to reduce ECM structural rigor, and 3) To examine the actin filamentous network as a central signaling mechanism whereby ECM integrity or stiffness impacts myocyte growth in vivo. Collectively, these specific aims will uncover how fibroblasts communicate with cardiomyocytes in the heart through the ECM and its properties. Such an understanding will lay the foundation for future studies into specific therapeutic targets in treating longstanding fibrotic heart disease states or hypertrophy in general.

抽象的长期以来，心肌细胞一直是试图阐明该研究的主要重点心脏发展和疾病的基础监管方面。但是，最近非甲状腺细胞的参与可能与肌细胞同样重要在进行性发病机理期间有助于并控制心脏重塑与心力衰竭。更具体地说，心脏成纤维细胞及其转换的能力促进细胞外基质（ECM）生产，心室重塑和现在，纤维化反应被视为心脏生物学同样关键的调节剂。我们会在这里解决心脏中的成纤维细胞如何作为疾病和病理的关键决定因素重塑。我们已经开发了重要的遗传工具，这些工具专门针对成纤维细胞心脏，以便我们可以操纵这些细胞的活性。因此，这里我们现在可以测试活化成纤维细胞（肌纤维细胞）的新型假设是心脏的关键调节剂疾病过程，不仅涉及纤维化，而且涉及心肌中心肌细胞的能力适当地肥大。我们将测试成纤维细胞调节的更具体的假设心肌细胞必须感觉到心脏ECM和胶原蛋白的密度和完整性增加结构支持以在体内有效肥大。确实，我们进一步假设心肌细胞内的张力传感机制向外延伸至 ECM及其完整性或僵硬。该应用程序具有3个具体目标：1）增加心脏中胶原蛋白的结构严谨，以研究对心肌细胞肥厚的影响体内的生长潜力，2）在心脏中遗传损害I型胶原蛋白形成以减少 ECM结构严谨，3）检查肌动蛋白丝网网络作为中心信号 ECM完整性或刚度会影响体内肌细胞生长的机制。共同这些特定的目标将发现成纤维细胞如何与心脏中心肌细胞沟通通过ECM及其特性。这样的理解将为未来奠定基础研究特定治疗靶标在治疗长期纤维化心脏病态或肥大一般。