FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR

描述（由申请人提供）：成纤维细胞生长因子信号在心脏损伤和修复中的作用摘要在对损伤的反应中，如在心血管疾病（CVD）的情况下，细胞和组织经常重新激活发育信号通路来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，有必要了解正常的发育途径以及它们如何在成人组织中被重新激活。在本研究中，我们将重点关注成纤维细胞生长因子（Fgfs），它是胚胎心脏发育、新生儿心肌生长和心肌损伤反应所必需的。发育和病理研究表明，心肌细胞、心外膜细胞和源自心外膜的细胞与心脏的血管成分之间存在重要的相互作用。最近的证据表明，FGF信号通路在心脏发育和对损伤的反应过程中调节心脏的所有三个组成部分。心外膜或心肌组织中FGF信号的丢失会损害正常发育并导致心脏大小减小。人类和小鼠的心脏损伤后，FGF信号通路增加，表明FGF信号通路可能是心脏修复所必需的。心肌梗死后，缺乏Fgf2的心脏表现为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下降，心肌细胞肥大减少，最终梗死面积增加（梗死扩张），心功能受损。与WT型心脏相比，心肌细胞中过表达Fgf2的转基因小鼠梗死面积减小，功能恢复加快。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信号在稳态、生理应激和损伤（心肌梗死）反应过程中调节心肌、心外膜源性和血管成分之间相互作用的分子、细胞和生理机制。我们建议：1)确定心脏保护所需的FGF2细胞靶点；2)验证FGF9和FGF16在成人心脏体内限制FGF活性的假设；3)确定调节新生儿、成人和损伤心肌细胞对FGFs反应的分子机制。这些研究将提供关于最有可能对FGF治疗有反应的cvd、对FGF有有益（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.