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肌细胞凋亡的研究的主要焦点。 心脏发育和疾病的潜在调节方面。然而，最近， 非肌细胞的参与可能与肌细胞一样重要， 促进和控制心脏重塑的进行性发病机制相关 心脏衰竭更具体地说，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）的产生，心室重塑和 纤维化反应现在被认为是心脏生物学的同样重要的调节剂。这里我们将 解决心脏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， 重塑我们已经开发出重要的遗传工具，专门针对成纤维细胞， 这样我们就可以控制这些细胞的活动。因此，我们现在可以测试 一种新的假说，即活化的成纤维细胞（肌成纤维细胞）是心脏的关键调节因子， 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 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脏ECM和胶原蛋白的密度和完整性， 增加结构支持，以有效地在体内肥大。事实上，我们进一步 假设心肌细胞内的张力感应机制向外延伸， ECM及其完整性或刚度。该应用程序有3个具体目标：1）增加 胶原蛋白在心脏中的结构严谨性，以探讨对心肌细胞肥大的影响 2）在遗传上损害心脏中I型胶原蛋白的形成，以减少 ECM结构的严谨性，以及3）检查肌动蛋白丝状网络作为中央信号传导 ECM完整性或刚度影响体内肌细胞生长的机制。总的来说， 这些特定的目标将揭示心脏中的成纤维细胞如何与心肌细胞沟通， 通过ECM及其属性。这样的理解将为未来奠定基础。 研究治疗长期纤维化心脏病状态的特定治疗靶点， 总体上是肥大

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.