FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR

成纤维细胞生长因子信号在心脏损伤和修复中的作用 总结 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。这可以导致有益的和 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。在这一提议中， 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 心肌生长和对心肌损伤的反应。 发育和病理学研究表明心肌细胞之间的重要相互作用， 心外膜细胞和源自心外膜的细胞，以及心脏的血管成分。最近的证据 表明FGF信号通路在发育过程中调节心脏的所有三个组成部分， 在对伤害的反应中。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 信号增加，表明FGF信号通路可能是心脏修复所必需的。以下 心肌梗死，缺乏Fgf 2的心脏显示成纤维细胞增殖和胶原沉积减少， 降低内皮细胞增殖和血管密度，降低心肌细胞肥大，增加 最终梗死面积（梗死扩大）和受损的心脏功能。过表达Fgf 2的转基因小鼠， 与WT心脏相比，心肌细胞具有减小的梗死面积和增加的功能恢复。 这些研究表明内源性FGF 2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信号转导的分子，细胞和生理机制， 调节心脏的心肌、心外膜衍生和血管成分之间的相互作用， 稳态、生理应激和对损伤的反应（心肌梗塞）。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在心脏保护中起作用的假设。 体内在成人心脏中限制FGF活性; 3）确定调节心肌细胞的分子机制 在新生儿、成人和损伤的心肌细胞中对FGF的反应性。 这些研究将提供关于最有可能对FGF反应的CVD的重要新信息， 基于治疗的细胞类型，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。这些知识 对于有效设计和实施用于治疗人CVD的基于FGF的疗法将是至关重要的。

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.