Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

心脏形态发生中的激活素受体样激酶 2

• 批准号: 6702655
• 负责人: VESA M KAARTINEN
• 金额: $ 29.27万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702655
• 关键词: activins; biological signal transduction; bone morphogenetic proteins; cardiogenesis; cell differentiation; cell growth regulation; cell proliferation; congenital heart disorder; genetic transcription; genetically modified animals; growth factor receptors; laboratory mouse; microarray technology; morphology; neural crest; protein structure function; transforming growth factors

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.

描述（由申请人提供）：心血管系统畸形是人类最常见的出生缺陷之一。分泌生长因子的进化保守的TGF-β超家族的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; Alks）发出信号，这是信号特异性的主要决定因素。在这些受体中，AIk 2是特别感兴趣的，因为似乎AIk 2介导BMP、激活素和TGF β信号。AIk 2在心脏中强烈表达，我们的初步实验表明，AIk 2是正常心脏发育所必需的。 因此，我们假设AIk 2通过调节心脏神经嵴细胞的分化、增殖和/或存活在心脏流出道发育中发挥关键作用。 我们将利用我们最近开发的基因操作小鼠品系，通过三个特定目的来测试这一假设，该小鼠品系允许在神经嵴细胞中特异性地失活AIk 2。在目标1中，将详细分析瓣膜、隔和流出道的缺陷。在目标2中，我们将定义在心脏流出道形态发生过程中AIK 2控制的特定过程，在目标3中，我们将确定相关的下游信号分子，Smads和AIK 2介导的通路中的转录靶点。 我们的实验策略将使我们能够确定AIK 2在心脏流出道发育中的生物学作用。这些研究的结果很可能是至关重要的，试图达到我们的长期目标，了解危及生命的人类先天性心脏病的分子基础。