PDGF Receptor Signaling in Mammalian Development

哺乳动物发育中的 PDGF 受体信号传导

• 批准号: 7655215
• 负责人: Michelle D Tallquist
• 金额: $ 39.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655215
• 关键词: Adult; Affect; Alleles; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell physiology; Cells; Cellular biology; Characteristics; Coronary; Coronary artery; Data; Deposition; Development; Embryo; Embryonic Heart; Endothelial Cells; Epicardium; Epithelial Cells; Fibroblasts; Fibrosis; Goals; Healed; Heart; Heart Diseases; Heart Injuries; Injury; Knowledge; Methods; Mus; Muscle; Myocardial Infarction; Myocardium; Neural Crest; Outcome; PDGF receptor tyrosine kinase; PDGFRA gene; PDGFRB gene; Pathway interactions; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Population; Process; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Testing; Tissues; angiogenesis; cell type; healing; heart function; improved; information gathering; insight; loss of function; programs; public health relevance; receptor function; repaired; success

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.

描述（由申请人提供）：心血管疾病是美国的主要死亡原因之一，无法修复受损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，常见的结果是永久性肌肉损失。虽然大量的研究集中在扩张或产生心肌细胞以替代受损组织的能力上，但较少关注控制纤维化的有害影响和增强血管生成的有益影响。关于心外膜或心脏外层的额外信息可以提供对这些过程的见解。研究表明，心外膜细胞分化为心肌细胞，血管平滑肌细胞，内皮细胞和成纤维细胞，深入了解导致这些细胞群在胚胎心脏中形成的机制对于心脏损伤后编程成人心外膜产生这些细胞类型至关重要。血小板衍生生长因子（PDGF）信号通路对于正常心外膜发育至关重要，本提案的主要目标是发现PDGF如何指导心外膜细胞发育和分化。这一目标将使用小鼠中PDGF受体的心外膜特异性功能丧失等位基因来实现。本提案的具体目的是：1）确定PDGF受体在心外膜初始发育中的作用机制; 2）阐明冠状动脉血管平滑肌细胞和心脏成纤维细胞对PDGFR 2的需求; 3）确定心脏内成纤维细胞发育和功能是否需要PDGFR 1信号传导。了解PDGF受体在心外膜和心外膜衍生细胞中的功能机制将为管理心外膜细胞生物学的信号传导机制提供重要的见解，并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传导途径。公共卫生关系：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作用于负责这些问题的细胞。这项研究的目的是确定可以改变这些细胞类型的形成和功能的信号。这些信号的操纵可以改善心脏损伤的结果。这些研究的成功将为促进用于修复受损心脏和减少纤维化的治疗提供信息。