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，影响约1/100的新生儿。虽然最近在小鼠和人类中的研究已经确定了适当的心脏发育所需的几种不同的信号传导过程和转录调节因子，但对心脏形态发生期间这些因子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。我们以前已经证明，BMP I型受体Alk 2在心脏神经嵴细胞以及调节肺动脉分隔和内皮细胞转化（EndMT）的内皮细胞中起着关键作用，而其他研究人员已经证明，另一种I型受体介导的BMP信号传导称为Alk 3在心脏流出道分隔和内皮细胞转化中也起着关键的非冗余作用。此外，我们最近在患有CHD的人类患者中发现了Alk 2和Alk 3基因编码区的突变。然而，目前尚不清楚Alk 2和Alk 3介导的BMP信号传导途径如何相互作用和相互合作以调节EndMT，以及TGF-2信号传导如何通过Alk 5与BMP信号传导在此过程中协调。在这个建议中，我想测试的核心假设，即TGF-2和BMP信号的协调行动是需要适当的心内膜间质转化（EndMT）在哺乳动物心脏发育。在目的1中，我们提出确定通过BMP I型受体Alk 2、Alk 3在EndMT和内皮细胞垫发育中的协同信号传导，并且在目的2中，我们提出测试通过TGF-2-I型受体Alk 5的信号传导是否对BMP诱导的内皮细胞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信号在心脏发育过程中EMT中的作用。总的来说，所提出的实验可能是至关重要的，在试图了解人类内分泌缺陷的分子基础，并可能最终使我们能够开发可能的预防和/或治疗方法来治疗先天性心脏缺陷在胎儿期，并确定新的治疗目标，以治疗心脏病。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，影响约1/100的新生儿。拟议的研究通过所谓的骨形态发生蛋白的I型受体剖析了特定信号传导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，这使得AV瓣膜和隔升高。我们期望这些研究对于理解导致人类先天性心脏畸形的潜在分子机制具有重要意义。

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.