Signaling mechanisms and functions related to patho-physiology of vascular, lung and blood systems

项目总结： 我的实验室对了解两个信号的分子基础和功能很感兴趣 在信号转导中使用七种跨膜受体的通路。其中一个 通路由G蛋白偶联受体介导，另一通路由Wnt激活 蛋白质。我们一直在使用生化、分子和细胞生物学的组合， 转基因、基因组、蛋白质组、结构和化学生物学方法发现新的 并研究它们在体外和体内的功能。在此R35应用程序中， 我打算简化我们目前与NHBLI任务相关的四个研究项目 在一种筹资机制下。其中两个项目目前由NHBLI提供资金。这四个人 项目有：1)检验对称性的初始破缺可能来自PM的假设 PI4P极化是由于细胞附着导致质膜变形而引起的。 极化PM PI4P定义了“尾足”，从而定义了初始细胞极性，在此基础上进一步 化学吸引剂刺激的极化被延长。2)调查持续的 成纤维细胞迁移调控的信号通路及其在治疗中的作用 肺纤维化。3)研究胞吐增加是致病因素的假说。 CCM病的基础。4)研究MEKK3对NADPH的负性调节作用 氧化酶2(NOD2)与急性呼吸窘迫综合征的潜在治疗靶点 每个项目都具有很高的创新性，并将在各自的领域产生强大的影响。 此外，我们正在从这些高风险/高回报研究中产生新的线索 这包括基于CRISPR/Cas9和RNAi技术的功能基因组筛选。 因此，这一R35机制不仅可以简化我们的赠款申请，而且 管理，以便我们可以更好地将精力集中在研究上，同时也为我们提供了灵活性 全面有效地寻找来自这些高风险/高回报研究的新线索。 我们的记录有力地表明了我们准备好、有能力和成功地攻读这些学科 我们认为影响很大，尽管它们超出了我们的初衷。

Project Summary: My laboratory is interested in understanding molecular basis and functions for two signaling pathways that use seven transmembrane receptors in their signaling transduction. One of the pathways is mediated by G protein-coupled receptors, and the other is activated by Wnt proteins. We have been using a combination of biochemical, molecular and cell biological, transgenic, genomic, proteomic, structural and chemical biological approaches to discover novel signaling mechanisms and investigate their functions in vitro and in vivo. In this R35 application, I intend to streamline our current four research projects that are pertinent to NHBLI missions under one funding mechanism. Two of the projects are current funded by NHBLI. These four projects are: 1) To test the hypothesis that the initial break of the symmetry may arise from PM PI4P polarization caused by plasma membrane deformation as the result of cell attachment. Polarized PM PI4P defines the “uropod” and thus the initial cellular polarity, upon which further polarization stimulated by chemoattractants is extended. 2) To investigate the sustained signaling pathway for regulation of fibroblast migration and its therapeutic potential in treating pulmonary fibrosis. 3) To Investigate the hypothesis that increased exocytosis is a pathogenic basis for CCM disease. 4) To investigate MEKK3 as being a negative regulator of NADPH oxidase 2 (NOD2) and potential therapeutic target for acute respiratory distress syndrome. Each of the project is highly innovative and would exert a strong impact in their respective field. In addition, we are generating the new leads coming from these high risk/high reward studies that include functional genomic screens based on the CRISPR/Cas9 and RNAi technologies. Thus, this R35 mechanism would not only allow streamlining our grant application and management so that we can better focus our effort on research, but also afford us the flexibility to fully and efficiently pursue the new leads coming from these high risk/high reward studies. Our track record strongly indicates our readiness, capability, and success to pursue subjects that we deem to be of high-impact even though they fall outside our initial intents.