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

与血管、肺和血液系统病理生理学相关的信号传导机制和功能

• 批准号: 9244290
• 负责人: Dianqing Wu
• 金额: $ 91.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244290
• 关键词: Adult Respiratory Distress Syndrome; Applications Grants; Biochemical; Biological; Blood; Blood Vessels; CRISPR/Cas technology; Cell Polarity; Cell membrane; Cell-Matrix Junction; Cells; Chemicals; Chemotactic Factors; Disease; Exocytosis; Fibroblasts; Functional disorder; Funding; Funding Mechanisms; G-Protein-Coupled Receptors; Genomics; Heart; In Vitro; Laboratories; Lung; Mediating; Mission; Molecular; NADPH Oxidase; Pathogenicity; Pathway interactions; Physiological; Process; Proteomics; Pulmonary Fibrosis; RNA Interference; Readiness; Regulation; Research; Research Project Grants; Signal Pathway; Signal Transduction; System; Technology; Testing; Therapeutic; Transgenic Organisms; Wnt proteins; base; falls; flexibility; functional genomics; high reward; high risk; in vivo; innovation; insight; interest; migration; novel; receptor; success; therapeutic target

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.

项目概要： 我的实验室有兴趣了解两种信号传导的分子基础和功能 在信号转导中使用七种跨膜受体的途径。之一 一条途径由G蛋白偶联受体介导，另一条途径由Wnt激活 proteins.我们一直在使用生物化学，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来发现新的 信号转导机制，并研究其在体外和体内的功能。在此R35应用中， 我打算精简我们目前的四个与NHBLI任务有关的研究项目 一个融资机制。其中两个项目目前由NHBLI资助。这四 主要工作有：1）验证对称性的初始破缺可能是由PM引起的假设 由细胞附着导致的质膜变形引起的PI 4P极化。 极化的PM PI 4P定义了“尾足动物”，并因此定义了初始细胞极性，在此基础上进一步 由化学引诱物刺激的极化被延长。2)为了调查持续的 调节成纤维细胞迁移的信号通路及其在治疗 肺纤维化。3)研究胞吐作用增加是一种致病性 CCM疾病的基础。4)研究MEKK 3作为NADPH的负调节剂 氧化酶2（NOD 2）是急性呼吸窘迫综合征的潜在治疗靶点。 每一个项目都具有很强的创新性，并将在各自的领域产生重大影响。 此外，我们正在从这些高风险/高回报研究中产生新的线索 包括基于CRISPR/Cas9和RNAi技术的功能基因组筛选。 因此，这种R35机制不仅可以简化我们的赠款申请， 管理，以便我们能够更好地集中精力进行研究，但也为我们提供了灵活性， 充分和有效地追求来自这些高风险/高回报研究的新线索。 我们的业绩记录有力地表明了我们在追求主题方面的准备、能力和成功 我们认为是高影响力的，即使它们超出了我们最初的意图。