FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR

成纤维细胞生长因子在心脏损伤修复中的信号转导 摘要 作为对损伤的反应，就像心血管疾病(CVD)一样，细胞和组织经常重新激活 修复损伤或再生组织的发育信号通路。这可能会带来有益的和 有害的后果。为了以有益的方式操纵伤害反应机制，至关重要的是 了解正常的发育途径以及它们是如何在成人组织中重新激活的。在这份提案中， 我们的重点是成纤维细胞生长因子(FGFs)，它是胚胎心脏发育、新生儿 心肌生长和对心肌损伤的反应。 发育和病理研究表明，心肌细胞之间存在重要的相互作用， 心外膜细胞和起源于心外膜的细胞，以及心脏的血管成分。最近的证据 提示成纤维细胞生长因子信号通路在心脏发育和发育过程中调节心脏的所有三个组成部分 在对受伤的反应中。心外膜或心肌组织中成纤维细胞生长因子信号的丢失损害正常 发育并导致心脏缩小。在人和小鼠心脏损伤后，成纤维细胞生长因子 信号转导增加，提示成纤维细胞生长因子信号通路可能是心脏修复所必需的。跟随 心肌梗死，缺乏FGF2的心脏表现为成纤维细胞增殖和胶原沉积减少， 减少血管内皮细胞增殖和血管密度，减少心肌细胞肥大，增加 最终的梗塞面积(梗塞扩大)和心功能受损。高表达FGF2的转基因小鼠 与WT心脏相比，心肌细胞缩小了梗塞面积，促进了功能的恢复。 这些研究表明，内源性FGF2在心脏对缺血损伤的反应中起着重要作用。 在这里，我们将探索成纤维细胞生长因子信号转导的分子、细胞和生理机制 调节心脏的心肌、心外膜来源和血管成分之间的相互作用 动态平衡、生理应激和损伤反应(心肌梗死)。我们建议：1)确定 心肌保护所需的FGF2的细胞靶点；2)检验FGF9和FGF16在 在成人心脏体内限制成纤维细胞生长因子的活性；3)确定调节心肌细胞的分子机制 新生、成人和受损心肌细胞对FGFs的反应性。 这些研究将提供关于最有可能对成纤维细胞生长因子有反应的心血管疾病的重要新信息。 基于治疗，预期对FGFs表现出有益(或有害)反应的细胞类型，以及 在潜在的内源性抑制物的背景下调节成纤维细胞生长因子活性的机制。这一知识 对于有效地设计和实施基于成纤维细胞生长因子的治疗人类心血管疾病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.