PDGF Receptor Signaling in Mammalian Development

描述(申请人提供)：心血管疾病是美国主要的死亡原因之一，而无法修复受损的肌肉是治疗心脏病的主要障碍。目前，还没有明确的方法来改善心脏病发作后的心脏功能，一个常见的结果是永久性的肌肉损失。虽然大量的研究集中在扩增或生成心肌细胞以替代受损组织的能力上，但对控制纤维化的有害影响和增强血管生成的有益影响的关注较少。关于心外膜或心脏外层的更多信息可能会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、血管平滑肌细胞、内皮细胞和成纤维细胞，深入了解这些细胞群在胚胎心脏中形成的机制将是在心脏损伤后编程使成人心外膜产生这些细胞类型的关键。血小板衍生生长因子(PDGF)信号通路对于正常的心外膜发育至关重要，本研究的主要目的是探索PDGF如何调控心外膜细胞的发育和分化。这一目标将使用小鼠的PDGF受体的心外膜特异性功能丧失等位基因来实现。这一建议的具体目的是：1)确定PDGF受体在心外膜最初发育过程中的作用机制；2)阐明冠状动脉血管平滑肌细胞和心脏成纤维细胞对PDGFR2的需求；以及3)确定心脏内成纤维细胞的发育和功能是否需要PDGFR1信号。了解PDGF受体在心外膜和心外膜衍生细胞中的功能机制，将有助于深入了解调控心外膜细胞生物学的信号机制，并有可能揭示可用于控制心脏损伤后纤维化和直接血管生成的信号通路。公共卫生相关性：心脏纤维化和冠状动脉功能受损是心脏病的两个主要特征，但很少有药物或疗法被确定对导致这些问题的细胞起作用。这项研究的目标是识别能够改变这些细胞类型的形成和功能的信号。操纵这些信号可以改善心脏损伤的结局。这些研究的成功将为推进用于修复受损心脏和减少纤维化的治疗提供信息。

DESCRIPTION (provided by applicant): 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 PDGFR2 in coronary vascular smooth muscle cells and cardiac fibroblasts; and 3) To determine if PDGFR1 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. PUBLIC HEALTH RELEVANCE: Cardiac fibrosis and impaired coronary artery function are two major features of heart disease, but few drugs or therapies have been identified that act upon the cells responsible for these problems. The goal of this research is to identify signals that can alter the formation and function of these cell types. Manipulation of these signals could improve the outcomes of cardiac injury. The success of these studies will provide information to advance the treatments used in repairing damaged hearts and reducing fibrosis.