Regulation of AV canal formation by the Jak-STAT pathway

描述(由申请人提供)：心血管异常是观察到的最常见的先天性出生缺陷之一。在这些异常中，很大一部分表现为房室管发育所形成的结构的改变。我们已经确定JAK-STAT信号转导通路在房室管的形成中起着调节作用。我们的数据显示，JAK-STAT通路的许多成员定位于房室管，通过阻断JAK3的功能，我们可以抑制正常的房室管的形成。这一建议试图通过以下几个方面深入了解房室管中调控这一通路的分子相互作用：(1)确定该通路的哪些STAT成员在房室管中是活跃的；(2)确定该通路的上游激活物及其在调控房室管形态发生中的作用部位(S)。通过利用三维胶原胶生物测定和最新的基因打靶技术，如反义寡核苷酸、吗啉、RNAi和功能扰动化学调节剂，抑制特定的JAK和STAT分子，我们打算检验以下假设：JAK-STAT通路的激活控制适当的房室通道的形成，并反映在转化过程的关键标记的表达上。我们的信条将在以下目标中得到检验。目的1：研究房室管形态发生过程中上皮细胞向间充质细胞转化(EMT)过程中激活的STAT成员的特性。目的2：建立JAK-STAT通路在EMT过程中起调节作用的精确组织，即心肌或内皮。目的：确定通过IL-2R途径发挥作用的JAK3上游激活物。

DESCRIPTION (provided by applicant): Cardiovascular anomalies represent one of the most prevalent congenital birth defects observed. Of these anomalies, a significant proportion manifest as an alteration in the formation of structures derived from the development of the atrioventricular (AV) canal. We have identified the Jak-STAT signal transduction pathway as playing a role in regulating the formation of the AV canal. Our data show that numerous members of the Jak-STAT pathway are localized to the AV canal, and that by blocking the function of Jak3 we can inhibit normal AV canal formation. This proposal seeks to gain insight into the molecular interactions that regulate this pathway in the AV canal by: (1) determining which STAT members of the pathway are active in the AV canal; and (2) identifying the upstream activators of the pathway and their site(s) of action in regulating the morphogenesis of the AV canal. By exploiting the use of 3-dimensional collagen gel bioassay and recent gene targeting techniques, such as antisense oligonucleotides, morpholinos, RNAi and function-perturbing chemical modulators, to inhibit specific Jak and STAT molecules we intend to test the following hypothesis: that activation of the Jak-STAT pathway controls proper AV canal formation and is reflected in the expression of key markers of the transformation process. Our tenets will be tested in the following aims. Aim 1: Characterize the specific STAT members of the pathway activated in epithelial to mesenchymal cell transformation (EMT) that occurs during AV canal morphogenesis. Aim 2: Establish the precise tissue in which the Jak-STAT pathway is functioning in regulation of the EMT process, i.e. myocardium or endothelium. Aim3: Identify the upstream activators of Jak3 that function through the IL-2R pathway.