Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

描述(申请人提供)：心血管系统畸形是人类最常见的先天缺陷之一。进化保守的转化生长因子-β超家族成员已被证明在正常心脏发育过程中发挥重要作用。它们都通过几种不同的I型受体(称为激活素受体样激酶；ALK)传递信号，这些受体是信号特异性的主要决定因素。在这些受体中，AIk2尤其令人感兴趣，因为AIk2似乎同时介导BMP、激活素和转化生长因子β信号。AIk2在心脏中强烈表达，我们的初步实验表明，AIk2是正常心脏发育所必需的。 因此，我们推测AIk2通过调节心脏神经脊细胞的分化、增殖和/或存活，在心脏流出道发育中起关键作用。 我们将利用我们最近开发的一种基因操纵的小鼠品系，通过三个特定的目标来检验这一假设，这种品系允许AIk2在神经脊细胞中特异地失活。在目标1中，将详细分析阀门、隔板和流出通道中的缺陷。在目标2中，我们将定义AIk2在心脏流出道形态发生过程中控制的特定过程，在目标3中，我们将确定AIk2介导的途径中相关的下游信号分子、Smads和转录靶标。 我们的实验策略将使我们能够确定AIk2在心脏流出道发育中的生物学作用。这些研究的结果可能对我们实现长期目标--了解威胁人类生命的先天性心脏病的分子基础--具有至关重要的意义。

DESCRIPTION (provided by applicant): Malformations of the cardiovascular system are among the most common birth defects in humans. Members of the evolutionary conserved TGF-beta superfamily of secreted growth factors have been shown to play important roles during normal heart development. They all signal through several different type I receptors (called Activin Receptor-Like Kinases; Alks), which are the primary determinants of signaling specificity. Among these receptors AIk2 is of particular interest, since it appears that AIk2 mediates both BMP, Activin and TGFbeta signals. AIk2 is strongly expressed in the heart, and our preliminary experiments demonstrate that AIk2 is required for normal cardiac development. Therefore, we hypothesize that AIk2 plays a key role in cardiac outflow tract development by regulating differentiation, proliferation and/or survival of cardiac neural crest cells. We will test this hypothesis by three Specific Aims by utilizing a genetically manipulated mouse strain we recently developed that allows inactivation of AIk2 specifically in neural crest cells. In Aim 1, defects in valves, septa and outflow tracts will be analyzed in detail. In Aim 2, we will define the specific process controlled by AIk2 during cardiac outflow tract morphogenesis, and in Aim 3 we will identify the relevant downstream signaling molecules, Smads, and transcriptional targets in the AIk2-mediated pathway. Our experimental strategy will allow us to determine the biological role of AIk2 in cardiac outflow tract development. The results of these studies are likely to be of critical importance in attempting to reach our long-term goal to understand the molecular basis of life-threatening congenital heart defects in humans.