Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

描述（由申请人提供）：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1个。虽然最近在小鼠和人类中的研究已经确定了心脏发育所需的几种不同的信号过程和转录调节因子，但对于心脏形态发生过程中这些因素之间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。我们之前已经证明，BMP I型受体Alk2在心脏神经嵴细胞以及调节主动脉-肺分隔和心内膜转化（EndMT）的心内膜细胞中都起着关键作用，而其他研究人员已经证明，另一种介导BMP信号传导的I型受体Alk3在心脏流出道分隔和心内膜转化中也起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，以及在此过程中通过Alk5介导的TGF-2信号如何与BMP信号协调。在这个提议中，我想验证一个中心假设，即在哺乳动物心脏发育过程中，TGF-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- 1型受体Alk2、Alk3在EndMT和心内膜缓冲发育中的协同信号传导，在目标2中，我们建议测试通过tgf -2- 1型受体Alk5的信号传导是否对BMP诱导的心内膜EMT至关重要。我们独特的实验模型和最先进的策略将使我们能够确定Tgf-2/Bmp信号在心脏发育期间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至关重要，并可能最终使我们能够开发可能的预防和/或治疗方法来治疗胎儿期先天性心脏缺陷，并确定治疗心脏病的新治疗靶点。公共卫生相关性：先天性心脏畸形是人类最常见的出生缺陷，约占新生儿的1 / 100。拟议的研究剖析了通过所谓的骨形态发生蛋白I型受体的特定信号机制在心脏形态发生中的作用，特别是在房室（AV）管的发育中，房室管产生房室瓣膜和间隔。我们期望所提出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.