PDGF Receptor Signaling in Mammalian Development

项目摘要 心血管疾病是美国死亡的主要原因之一， 受损的肌肉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，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大或产生的能力， 由于心肌细胞用于替换受损组织，较少关注控制心肌细胞的生长， 纤维化的有害作用和增强血管生成的有益作用。额外 关于心外膜或心脏外层的信息可以提供对这些过程的了解。 研究表明，心外膜细胞分化为心肌细胞，血管光滑， 肌肉细胞，内皮细胞和成纤维细胞，以及深入了解 使这些细胞群在胚胎心脏中形成， 成人心外膜在心脏损伤后产生这些细胞类型。血小板衍生生长因子（PDGF） 信号传导通路对于正常的心外膜发育是必不可少的， 这项研究的目的是发现PDGF如何指导心外膜细胞的发育和分化。这一目标 将通过使用血小板膜中PDGF受体的心外膜特异性功能丧失等位基因来实现。 老鼠.本研究的具体目的是：1）明确PDGF受体的作用机制 在心外膜的初始发育中的作用; 2）为了阐明PDGFR的需求， 冠状动脉血管平滑肌细胞和心脏成纤维细胞;和3）为了确定是否PDGFR？ 信号传导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功能机制将提供 对心外膜细胞生物学信号传导机制的重要见解， 揭示了信号通路，可以操纵，以控制纤维化和直接血管生成后， 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.