Type III Transforming Growth Factor beta Receptor in Coronary Vessel Development

描述(申请人提供)：冠状动脉疾病占美国所有心血管疾病的54%[1]。了解冠状动脉如何发展可能会发现新的药物靶点和治疗策略，有助于指导成人冠状动脉的修复或重塑。我们实验室的最新数据表明，靶向缺失III型转化生长因子2受体(TGF2R3)会导致胚胎死亡，并伴随着冠状动脉形成或持续的失败，而其他血管床似乎发育正常。实验旨在确定TGF2R3的缺失如何导致冠状动脉发育失败，并揭示调控心外膜细胞分化的TGF2信号通路。我们将检验3个具体的假设。假设1：TGF2R3是心外膜正常分化所必需的。这将通过对野生型、杂合子Tgfbr3缺失和纯合子Tgfbr3缺失动物的心外膜和心外膜衍生物的体内分析来验证。假设2：TGF2R3在心外膜或心肌中是冠状动脉正常发育所必需的。这将通过有条件地删除心外膜和心肌中的Tgfbr3来进行测试。假设3：特定的TGF2信号通路调节心外膜细胞分化。这将在体外对野生型、杂合子Tgfbr3缺失和纯合子Tgfbr3缺失动物的外植体和永生化细胞进行测试。拟议中的实验的成功完成将对转化生长因子2(TGF2)在冠状动脉发育中的作用产生重要的影响。冠脉起源的独特性质和冠状动脉疾病的重要性使得从基础科学和临床角度确定TGF2R3调控冠脉血管生成的机制具有重要意义。

DESCRIPTION (provided by applicant): Coronary artery disease accounts for 54% of all cardiovascular disease in the United States [1]. Understanding how coronary vessels develop is likely to uncover novel drug targets and therapeutic strategies useful in directing the repair or remodeling of coronary vessels in adults. Recent data from our laboratory has demonstrated that targeted deletion of the Type III Transforming Growth Factor 2 receptor (TGF2R3) results in embryonic death associated with failure of the formation or persistence of the coronary vessels while other vascular beds appear to develop normally. Experiments are proposed to identify how the loss of TGF2R3 results in the failure of coronary vessel development and to reveal the TGF2 signaling pathways that regulate epicardial cell differentiation. We will test 3 specific hypotheses. Hypothesis 1: TGF2R3 is required for proper epicardial differentiation. This will be tested by in vivo analysis of the epicardium and epicardial derivatives in wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals. Hypothesis 2: TGF2R3 is required in the epicardium or myocardium for proper coronary vessel development. This will be tested by conditional deletion of Tgfbr3 in the epicardium and myocardium. Hypothesis 3: Specific TGF2 signaling pathways regulate epicardial cell differentiation. This will be tested in vitro in both explants and immortalized cells from wildtype, heterozygous Tgfbr3 null, and homozygous Tgfbr3 null animals The successful completion of the proposed experiments will yield significant insight into the role of Transforming Growth Factor 2 (TGF2) in coronary vessel development. The unique nature of the derivation of the coronary vessels and the significance of coronary vessel disease in humans makes the determination of the mechanisms behind TGF2R3 regulation of coronary vasculogenesis of high significance from both a basic science and clinical perspective.