ALK5 AND ALK3 SIGNALING AND FUNCTION IN THE EMBRYONIC HEART

β型转化生长因子（TGF β）和相关细胞因子 包括骨形态发生蛋白（BMP）在内的骨与多种 心血管发育、功能障碍和疾病方面，包括 心肌发生本身和身体轴的建立。目前， 这种情况在很大程度上取决于从鸟类外植体的推断， 其他异源模型系统。小鼠遗传学在 TGF β在体内的信号传导已经被广泛的 家庭成员之间的冗余，并通过母体抢救（经胎盘 交付）。TGF β家族成员的信号转导涉及配对的 跨膜丝氨酸-苏氨酸激酶：II型受体结合配体 以高亲和力，然后磷酸化I型受体（激活素 受体样激酶，或ALK蛋白），其介导下游 方面的影响. TGF β和BMP受体信号传导的两种建议途径 涉及TGF β/BMP活化激酶和Smad转录因子; 然而，不知道这些是串联还是并联操作 (i.e.,对于不同的效应子集）。最近，我们开发了一种 I型受体ALK 5的组成性激活形式，指导其 表达的胚胎心肌，并表明，组成 通过ALK 5的信号传导阻止小鼠中的成环形态发生。 本项目的具体目标是： .使用胚胎致死ALK 5基因的条件激活，研究 阻止环状形态发生的分子机制。 .为了测试TAK和Smad蛋白在信号传导中的功能作用， ALK 5，体外和体内。 .使用心脏限制性表达或条件性诱导Cre 重组酶，以测试内源性ALK 5和ALK 3在早期肿瘤中的功能。 老鼠心脏

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.