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个跨膜受体的途径。中的一个 一条通路由G蛋白偶联受体介导，另一条由Wnt激活 蛋白质。我们一直在使用生化、分子和细胞生物学的结合， 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 信号机制并研究其在体外和体内的功能。在此 R35 应用中， 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 资助。这四个 项目有： 1) 检验对称性初始破缺可能由 PM 引起的假设 PI4P 极化是由细胞附着导致的质膜变形引起的。 极化 PM PI4P 定义了“尾足动物”，从而定义了初始细胞极性，在此基础上进一步 化学引诱剂刺激的极化延长。 2）调查持续 成纤维细胞迁移调节的信号通路及其治疗潜力 肺纤维化。 3) 调查胞吐作用增加是致病因素的假设 CCM 疾病的基础。 4) 研究MEKK3作为NADPH的负调节因子 氧化酶 2 (NOD2) 和急性呼吸窘迫综合征的潜在治疗靶点。 每个项目都具有高度创新性，并将在各自领域产生强大影响。 此外，我们正在从这些高风险/高回报的研究中产生新的线索 其中包括基于 CRISPR/Cas9 和 RNAi 技术的功能基因组筛选。 因此，这个 R35 机制不仅可以简化我们的拨款申请， 管理使我们能够更好地专注于研究，同时也为我们提供了灵活性 充分有效地寻求来自这些高风险/高回报研究的新线索。 我们的记录有力地表明了我们在追求学科方面的准备、能力和成功 我们认为具有很大影响力，尽管它们不符合我们最初的意图。