ALK5 AND ALK3 SIGNALING AND FUNCTION IN THE EMBRYONIC HEART

β-型转化生长因子及其相关细胞因子 包括骨形态发生蛋白(BMP)在内的多种与骨骼有关的物质 心血管发育、功能障碍和疾病的方面，包括 心肌发生本身，以及体轴的建立。目前， 这种情况在很大程度上取决于从鸟类外植体和 其他异源模型系统。小鼠遗传学在生物遗传研究中的应用 体内的转化生长因子β信号已经被广泛的 家庭成员之间的冗余，以及母亲的抢救(经胎盘 交付)。转化生长因子β家族成员的信号转导涉及配对 跨膜丝氨酸苏氨酸激酶：II型受体与配体结合 高亲和力，然后磷酸化I型受体(激活素 受体样激酶，或ALK蛋白)，它们介导下游 效果。转化生长因子β和骨形态发生蛋白受体信号传导的两条途径 涉及转化生长因子β/骨形态发生蛋白激活的激酶和Smad转录因子； 然而，目前尚不清楚这些设备是串联运行还是并行运行 (即，对于不同的效果子集)。最近，我们开发了一种 I型受体的成分激活形式，Alk5，引导其 在胚胎心肌中的表达，并表明构成 由Alk5发出的信号阻止了小鼠的环状形态发生。 本项目的具体目标是： 。利用胚胎致死的Alk5基因的有条件激活，研究 阻断到环状形态发生的分子机制。 。为了测试TAK和Smad蛋白在信号转导中的功能作用 Alk5，体外和体内。 。使用心脏限制性表达或有条件地诱导Cre 重组酶，检测早期内源性Alk5和Alk3的功能 老鼠的心。

Type beta transforming growth factor (TGFbeta) and related cytokines including bone morphogenic proteins (BMPs) have bone implicated in diverse aspects of cardiovascular development, dysfunction, and disease including cardiac myogenesis itself, and establishment of the body axes. At present, this case is largely contingent on extrapolation from avian explants and other heterologous model systems. The application of mouse genetics to TGFbeta signaling in vivo has been confounded both by the extensive redundancy among family members, and by maternal rescue (transplacental delivery). Signal transduction for TGFbeta family members involves paired membrane-spanning serine-threonine kinases: type II receptors bind ligand with high affinity, then phosphorylate the type I receptors (activin receptor-like kinases, or ALK proteins), which mediate the downstream effects. Two proposed pathways for TGFbeta and BMP receptor signaling involve the TGFbeta/BMP-activated kinase, and Smad transcription factors; however, it is unknown whether these operate in series or in parallel (i.e., for different subsets of effects). Recently, we have developed a constitutively activated form of the type I receptor, ALK5, directed its expression to the embryonic myocardium, and shown that constitutive signaling by ALK5 arrests looping morphogenesis in mice. Specific Aims of the present project are: . Using conditional activation of the embryonic-lethal ALK5 gene, to study molecular mechanisms for the block to looping morphogenesis. . To test the functional role of TAK and Smad proteins in signaling by ALK5, in vitro and in vivo. . Using cardiac-restricted expression or conditional induction of Cre recombinase, to test the function of endogenous ALK5 and ALK3 in the early mouse heart.