Dissecting the role of the cardiac fibroblast in hypertrophy.

摘要 长期以来，心肌细胞一直是试图阐明 心脏发育和疾病背后的调控方面。然而，最近， 非心肌细胞的参与已经成为与心肌细胞同样重要的潜在因素 在进展性发病机制中促进和控制心脏重构 并伴有心力衰竭。更具体地说，心脏成纤维细胞及其转化为 肌成纤维细胞在促进细胞外基质(ECM)产生、心室重构和心肌梗死中的作用 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 阐述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 改建。我们已经开发了重要的基因工具，专门针对成纤维细胞 心脏，这样我们就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说 疾病过程，不仅涉及纤维化，而且还涉及心脏中心肌细胞的能力 到适当的肥大。我们将测试更具体的假设，即成纤维细胞调节 心肌细胞必须感觉到的心肌细胞外基质和胶原的密度和完整性 增加结构支撑，才能有效地在体内肥大。事实上，我们进一步 假设心肌细胞内的张力感知机制向外延伸到 ECM及其完整性或刚性。这项申请有3个具体目标：1)增加 心脏胶原结构的刚性研究对心肌细胞肥大的影响 体内生长潜力，2)从基因上损害心脏I型胶原的形成，以减少 ECM结构严谨，以及3)检查肌动蛋白丝状网络作为中心信号 ECM完整性或僵硬影响体内心肌细胞生长的机制。总而言之， 这些特定的目标将揭示成纤维细胞如何与心脏中的心肌细胞进行交流 通过ECM及其特性。这样的认识将为未来奠定基础 治疗慢性纤维性心脏病状态的特异性靶点研究 一般都是肥大。

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.