Regulation of AV canal formation by the Jak-STAT pathway

Jak-STAT 通路对 AV 管形成的调节

• 批准号: 6720958
• 负责人: JAY D POTTS
• 金额: $ 31.06万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720958
• 关键词: JAK kinase; RNA interference; active sites; atrioventricular node; bioassay; biological signal transduction; cardiovascular disorder; cell transformation; cytokine receptors; embryo /fetus tissue /cell culture; enzyme activity; epithelium; gene targeting; genetically modified animals; histogenesis; immunocytochemistry; immunoprecipitation; interleukin 2; intermolecular interaction; laboratory mouse; mesenchyme; polymerase chain reaction; protein localization; western blottings

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.

描述（由申请人提供）：心血管异常是观察到的最普遍的先天性先天缺陷之一。在这些异常情况下，显着的比例表现为从心房（AV）运河的发展得出的结构形成的改变。我们已经确定JAK-STAT信号转导途径在调节AV运河的形成中起着作用。我们的数据表明，JAK-STAT途径的众多成员位于AV运河上，并且通过阻止JAK3的功能，我们可以抑制正常的AV运河形成。该提议试图通过以下方式深入了解在AV运河中调节该途径的分子相互作用：（1）确定该途径的哪些统计成员在AV运河中有效； （2）识别途径的上游激活因子及其在调节AV管的形态发生方面的作用位点。通过利用3维胶原凝胶生物测定和最新的基因靶向技术，例如反义寡核苷酸，吗啡，RNAI和功能扰动化学调节剂，抑制特定的JAK和Stat Molecules，我们打算测试以下的假设：AVAR的表达：AVAR的表达能力依次，即使在jak stat state Pates的表达中，AVAR的表达方式是AVAR的激活，并且转换过程的标记。我们的宗旨将在以下目标中进行测试。 AIM 1：表征在上皮细胞转化（EMT）中激活的途径的特定统计成员，该途径发生在AV管形态发生过程中。 AIM 2：建立JAK-STAT途径在EMT过程（即心肌或内皮）调节中起作用的精确组织。 AIM3：确定通过IL-2R途径发挥作用的JAK3的上游激活剂。