Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

描述(申请人提供)：先天性心脏畸形是人类最常见的出生缺陷，大约每100个新生儿中就有一个受到影响。虽然最近在小鼠和人类身上的研究已经确定了心脏适当发育所需的几个不同的信号过程和转录调节因子，但对于这些因素在心脏形态发生过程中的相互作用以及导致人类先天性心脏病(CHD)的发病机制仍然知之甚少。我们以前已经证明，BMP I型受体Alk2在心脏神经脊细胞以及心内膜细胞调节主-肺间隔和心内膜转换(EndMT)中都发挥着关键作用，而其他研究人员已经证明，另一种介导BMP信号转导的I型受体Alk3在心脏流出道间隔和心内膜转换中也发挥着关键的非冗余作用。此外，我们最近在人类冠心病患者中发现了Alk2和Alk3基因编码区的突变。然而，目前尚不清楚Alk2和Alk3介导的BMP信号通路如何相互作用和协同调节EndMT，以及Alk5介导的转化生长因子-2信号如何与BMP信号在这一过程中协调。在这项提议中，我想检验中心假设，在哺乳动物心脏发育过程中，转化生长因子-2和BMP信号的协同作用是适当的心内膜到间充质转化(EndMT)所必需的。在目标1中，我们建议确定通过BMP I型受体Alk2、Alk3在EndMT和心内膜垫发育中的协同信号，在目标2中，我们建议测试通过转化生长因子-2-I型受体Alk5的信号是否在BMP诱导的心内膜上皮细胞转化中起关键作用。我们独特的实验模型和最先进的策略将使我们能够确定转化生长因子-2/BMP信号在心脏发育过程中的EMT中的作用。总的来说，拟议的实验可能对试图了解人类心内膜缺陷的分子基础具有至关重要的作用，并最终可能使我们能够开发出可能的预防和/或治疗方法来治疗胎儿时期的先天性心脏缺陷，并确定治疗心脏病的新靶点。与公共卫生相关：先天性心脏畸形是人类最常见的出生缺陷，大约每100名新生儿中就有1人受到影响。这些研究通过所谓的骨形态发生蛋白的I型受体，剖析了特定的信号机制在心脏形态发生中的作用，特别是在房室管的发育过程中，房室瓣和房间隔的形成。我们期望拟议的研究对于理解导致人类先天性心脏畸形的潜在分子机制将是重要的。

DESCRIPTION (provided by applicant): Congenital cardiac malformations are the most common birth defects in humans affecting about 1 in 100 newborns. While recent studies both in mice and in humans have identified several different signaling processes and transcriptional regulators that are required for appropriate cardiac development, very little is still known about interactions between these factors during heart morphogenesis, and about pathogenetic mechanisms leading to the congenital heart disease (CHD) in humans. We have previously demonstrated that the BMP type I receptor Alk2 plays a critical role both in cardiac neural crest cells as well as in endocardial cells regulating aortico-pulmonary septation and endocardial transformation (EndMT), while other investigators have demonstrated that another type I receptor mediating BMP signaling called Alk3 is playing a critical non-redundant role in cardiac outflow tract septation and endocardial transformation as well. Moreover, we have recently discovered mutations in the coding region of Alk2 and Alk3 genes in human patients suffering from CHD. However, it is currently not known, how Alk2 and Alk3-mediated BMP signaling pathways interact and cooperate with each other to regulate EndMT and how TGF-2 signaling via Alk5 is coordinated with BMP signaling in this process. In this proposal I want to test the central hypothesis that that concerted action of TGF-2 and BMP signaling is required for appropriate endocardial-to-mesenchymal transformation (EndMT) during mammalian cardiac development. In aim 1 we propose to determine the collaborative signaling via the BMP type I receptors Alk2, Alk3 in EndMT and endocardial cushion development, and in aim 2 we propose to test whether signaling via the TGF-2-type I receptor Alk5 is critical for BMP-induced endocardial EMT. Our unique experimental models and state-of-art strategy will allow us to determine the role Tgf-2/Bmp signaling in EMT during cardiac development. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular bases of endocardial defects in humans, and may ultimately allow us to develop possible preventive and/or therapeutic approaches to treat congenital cardiac defects during the fetal period and to identify new therapeutic targets to treat heart disease. PUBLIC HEALTH RELEVANCE: Congenital cardiac malformations are the most common birth defects in humans affecting about 1 in 100 newborns. The proposed studies dissect the role of specific signaling mechanisms via the so called type I receptors of bone morphogenetic proteins in cardiac morphogenesis, particularly in the development of atrio-ventricular (AV) canal, which gives raise to AV valves and septa. We expect that the proposed studies will be important for understanding of the underlying molecular mechanisms that lead to congenital cardiac malformations in humans.