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：
10514028
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/10514028
关键词：
Actins Acute Address Adhesions Adult Biology Cardiac Cardiac Myocytes Cardiac development Cells Characteristics Collagen Collagen Fibril Collagen Type I Complementary DNA Complex Data Defect Disease Dystroglycan Extracellular Matrix F-Actin Fibroblasts Fibrosis Focal Adhesions Foundations Future Generations Genes 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 Reporter Role Signal Pathway Signal Transduction Tamoxifen Testing Transforming Growth Factor beta Receptors Transgenic Mice Ventricular Remodeling beta Actin beta catenin coronary fibrosis crosslink density gamma Actin genomic locus healing heart function in vivo mouse model novel novel therapeutics paracrine periostin pressure protein aggregation response therapeutic target three dimensional cell culture tool

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其机制的研究的主要焦点。心脏发育和疾病的调节方面。然而，最近非肌细胞的参与可能与肌细胞的参与一样重要在进行性发病机制相关的过程中促进和控制心脏重塑患有心力衰竭。更具体地说，心脏成纤维细胞及其转化为肌成纤维细胞促进细胞外基质（ECM）产生、心室重塑和纤维化反应现在被视为心脏生物学的一个同样重要的调节因素。在这里我们将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发挥作用重塑。我们开发了重要的遗传工具，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动。因此，我们现在可以在这里测试激活的成纤维细胞（肌成纤维细胞）是心脏的关键调节因子的新假设疾病过程，不仅涉及纤维化，还涉及心脏中心肌细胞的能力才能适当肥大。我们将测试更具体的假设，即成纤维细胞调节心肌细胞必须感知的心脏 ECM 和胶原蛋白的密度和完整性增加结构支撑，以便体内有效肥大。确实，我们进一步假设心肌细胞内的张力感应机制向外延伸到 ECM 及其完整性或刚度。该应用程序有 3 个具体目标：1) 增加心脏中胶原蛋白的结构严谨性，研究对心肌细胞肥大的影响体内生长潜力，2) 从遗传上损害心脏中 I 型胶原蛋白的形成，以减少 ECM 结构严谨性，以及 3) 检查肌动蛋白丝状网络作为中央信号传导 ECM 完整性或硬度影响体内肌细胞生长的机制。总的来说，这些具体目标将揭示成纤维细胞如何与心脏中的心肌细胞沟通通过 ECM 及其特性。这样的认识将为以后打下基础研究治疗长期纤维化心脏病的特定治疗靶点或普遍肥大。