PDGF Receptor Signaling in Mammalian Development

项目摘要 心血管疾病是美国人死亡的主要原因之一，而无法修复 肌肉受损是治疗心脏病的主要障碍。目前，还没有明确的 心脏病发作后改善心脏功能的方法，一个常见的结果是永久性肌肉 损失。虽然大量的研究都集中在扩展或生成 心肌细胞用于替代受损组织，较少关注于控制 对纤维化的不利影响和增强血管生成的有益影响。其他内容 关于心外膜或心脏外层的信息可能提供对这些过程的洞察。 研究表明，心外膜细胞可分化为心肌细胞，血管通畅 肌肉细胞、内皮细胞和成纤维细胞，并深入了解 使这些细胞群体在胚胎心脏中形成将是编程 成人心外膜在心脏损伤后产生这些类型的细胞。血小板衍生生长因子(PDGF) 信号通路对于正常的心外膜发育是必不可少的，其主要目标是 研究的目的是发现PDGFs如何指导心外膜细胞的发育和分化。这个目标 将使用心外膜特异的PDGF受体功能丧失等位基因来实现 老鼠。这项建议的具体目的是：1)确定PDGF受体的机制 在心外膜发育初期的作用；2)阐明对PDGFR的需求 冠状动脉血管平滑肌细胞和心脏成纤维细胞；3)确定PDGFR？ 信号是心脏内成纤维细胞发育和功能所必需的。了解 PDGF受体在心外膜和心外膜衍生细胞中的作用机制将提供 对调控心外膜细胞生物学和潜在的信号机制的重要见解 揭示可被操纵以控制纤维化和指导血管生成的信号通路 心脏损伤。

Project Summary Cardiovascular disease is one of the leading causes of death in the US, and the inability to repair damaged muscle is a major obstacle in treating heart disease. Currently, there are no definitive methods to improve heart function after a heart attack, and a common result is permanent muscle loss. While a significant amount of research has focused on the ability to expand or generate cardiomyocytes for replacement of the damaged tissue, less focus has been placed on controlling the detrimental effects of fibrosis and enhancing the beneficial effects of angiogenesis. Additional information on the epicardium, or outer layer of the heart, may provide insights into these processes. Studies have demonstrated that epicardial cells differentiate into cardiomyocytes, vascular smooth muscle cells, endothelial cells, and fibroblasts, and an in depth knowledge of the mechanisms that cause these cell populations to form in the embryonic heart will be essential for programming the adult epicardium to generate these cell types after heart injury. Platelet derived growth factor (PDGF) signaling pathways are essential for normal epicardial development, and the main goal of this proposal is to discover how PDGFs direct epicardial cell development and differentiation. This goal will be accomplished using epicardial-specific loss-of-function alleles of the PDGF receptors in the mouse. The specific aims of this proposal are: 1) To determine the mechanism of PDGF receptor action in the initial development of the epicardium; 2) To elucidate the requirement for PDGFR¿ in coronary vascular smooth muscle cells and cardiac fibroblasts; and 3) To determine if PDGFR¿ signaling is required for fibroblast development and function within the heart. Understanding the mechanisms of PDGF receptor function in the epicardium and epicardial derived cells will provide important insights into the signaling mechanisms governing epicardial cell biology and potentially reveal signaling pathways that could be manipulated to control fibrosis and direct angiogenesis after cardiac injury.