FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR

描述（由申请人提供）：心脏损伤和修复中的成纤维细胞生长因子信号传导概述响应于损伤，如在心血管疾病（CVD）的情况下，细胞和组织通常重新激活发育信号传导途径以修复损伤或再生组织。这可能导致有益和有害的后果。为了以有益的方式操纵损伤反应机制，必须了解正常的发育途径以及它们如何在成人组织中重新激活。在这项提案中，我们专注于成纤维细胞生长因子（Fgfs），这是必需的胚胎心脏发育，新生儿心肌生长和心肌损伤的反应。 发育和病理学研究表明，心肌细胞、心外膜细胞和心外膜细胞与心脏血管成分之间存在重要的相互作用。最近的证据表明，FGF信号通路在发育和对损伤的反应期间调节心脏的所有三个组成部分。心外膜或心肌组织中FGF信号传导的缺失损害正常发育并导致心脏尺寸减小。在人类和小鼠心脏损伤后，FGF信号传导增加，表明FGF信号传导途径可能是心脏修复所必需的。心肌梗死后，缺乏Fgf2的心脏显示成纤维细胞增殖和胶原沉积减少，内皮细胞增殖和血管密度减少，心肌细胞肥大减少，最终梗死面积增加（梗死扩大），心脏功能受损。与野生型心脏相比，在心肌细胞中过表达Fgf2的转基因小鼠具有减少的梗死面积和增加的功能恢复。这些研究表明内源性FGF2在心脏对缺血性损伤的反应中起重要作用。 在这里，我们将探讨FGF信号调节心肌，心外膜衍生和心脏血管成分之间的相互作用，在稳态，生理应激和损伤（心肌梗死）的反应的分子，细胞和生理机制。我们建议：1）确定心脏保护所需的FGF 2的细胞靶点; 2）测试FGF 9和FGF 16在成人心脏中体内发挥作用以限制FGF活性的假设; 3）确定调节新生儿、成人和受损心肌细胞中心肌细胞对FGF的反应性的分子机制。 这些研究将提供关于最有可能对基于FGF的治疗有反应的CVD、预期对FGF显示有益（或有害）反应的细胞类型以及在潜在内源性抑制剂的背景下调节FGF活性的机制的重要新信息。这些知识对于有效设计和实施用于治疗人类CVD的基于FGF的疗法至关重要。 公共卫生相关性：心脏损伤和修复中的成纤维细胞生长因子信号与公共卫生的相关性：心血管疾病占美国所有死亡人数的34%。为了应对损伤，例如心血管疾病，细胞和组织通常会重新激活发育信号通路以修复损伤或再生组织。为了理解并因此改变损伤反应机制，理解正常的发育途径至关重要。成纤维细胞生长因子（FGF）已被认为是心血管系统发育和功能的重要调节因子。本提案中的研究将推进我们对成人心脏中FGF信号通路的了解，并将确定在正常生理条件下以及心脏对缺血性损伤的反应期间如何使用和调节FGF信号通路。这些研究将提供关于哪些类型的心血管疾病最有可能对基于FGF的治疗产生反应，如何将FGF活性最佳地靶向正确的细胞，以及如何在潜在的内源性抑制机制的背景下调节FGF活性的基本知识。这些知识对于设计和实施有效的基于FGF的治疗人类心血管疾病的疗法至关重要。

DESCRIPTION (provided by applicant): Fibroblast Growth Factor signaling in heart injury and repair Summary In response to injury, as in the case of cardiovascular disease (CVD), cells and tissues often reactivate developmental signaling pathways to repair damage or regenerate tissue. This can result in both beneficial and harmful consequences. To manipulate injury response mechanisms in a beneficial way, it is essential to understand the normal developmental pathways and how they are reactivated in adult tissues. In this proposal, we focus on Fibroblast Growth Factors (Fgfs), which are required for embryonic heart development, neonatal myocardial growth and the response to myocardial injury. Developmental and pathological studies demonstrate important interactions between cardiomyocytes, epicardial cells and cells derived from the epicardium, and vascular components of the heart. Recent evidence suggests that FGF signaling pathways regulate all three components of the heart during development and during the response to injury. Loss of FGF signaling in either epicardial or myocardial tissues impairs normal development and results in decreased heart size. Following injury to the heart in both humans and mice, FGF signaling increases, indicating that FGF signaling pathways may be necessary for cardiac repair. Following myocardial infarction, hearts lacking Fgf2 show reduced fibroblast proliferation and collagen deposition, decreased endothelial proliferation and vascular density, decreased cardiomyocyte hypertrophy, increased final infarct size (infarct expansion), and impaired cardiac function. Transgenic mice that overexpress Fgf2 in cardiomyocytes have decreased infarct sizes and increased recovery of function compared to WT hearts. These studies indicate an essential role for endogenous FGF2 in the heart's response to ischemic injury. Here we will explore the molecular, cellular and physiological mechanisms by which FGF signaling regulates interactions between myocardial, epicardial-derived and vascular components of the heart during homeostasis, physiological stress and response to injury (myocardial infarction). We propose to: 1) Identify the cellular targets of FGF2 required for cardioprotection; 2) Test the hypothesis that FGF9 and FGF16 function in vivo in the adult heart to limit FGF activity; 3) Identify molecular mechanisms that regulate cardiomyocyte responsiveness to FGFs in neonatal, adult and injured cardiomyocytes. These studies will provide essential new information about CVDs that are most likely to respond to FGF- based therapy, cell types that would be expected to show a beneficial (or detrimental) response to FGFs, and the mechanisms that regulate FGF activity in the context of potential endogenous inhibitors. This knowledge will be essential to effectively design and implement FGF-based therapies for the treatment of human CVD. PUBLIC HEALTH RELEVANCE: Fibroblast Growth Factor signaling in heart injury and repair Public Health relevance: Cardiovascular disease accounts for 34% of all deaths in the United States. In response to injury, as in the case of cardiovascular disease, cells and tissues often reactivate developmental signaling pathways to repair damage or regenerate tissue. To understand and thus modify injury response mechanisms, it is essential to understand the normal developmental pathways. Fibroblast Growth Factors (FGFs) have been proposed as important regulators of development and function of the cardiovascular system. The research in this proposal will advance our knowledge of FGF signaling pathways in the adult heart and will determine how FGF signaling pathways are used and regulated under normal physiological conditions and during the response of the heart to ischemic injury. These studies will provide essential knowledge about which types of cardiovascular diseases are most likely to respond to FGF-based therapy, how to optimally target FGF activity to the correct cell(s), and how to regulate FGF activity in the context of potential endogenous inhibitory mechanisms. This knowledge will be essential to design and implement effective FGF-based therapies for the treatment of human cardiovascular diseases.