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: 10570974
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570974
• 关键词: Acute 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; Membrane; 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; 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.

项目摘要： 我的实验室有兴趣了解两个信号的分子基础和功能 在信号转导中使用七个跨膜受体的途径。中的一个 途径是由G蛋白偶联受体介导的，另一种是由Wnt激活的 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，蛋白质组学，结构和化学生物学方法可发现新型 信号传导机制并在体外和体内研究其功能。在此R35应用程序中 我打算简化与NHBLI任务有关的当前四个研究项目 在一种资金机制下。其中两个项目目前由NHBLI资助。这四个 项目是：1）检验以下假设：对称的初始断裂可能是从PM引起的 由细胞附着的质膜变形引起的PI4P极化。 极化PM PI4P定义了“ uropod”，因此定义了初始细胞极性，然后进一步 趋化因子刺激的极化扩大。 2）调查持续的 调节成纤维细胞迁移及其治疗潜力的信号通路 肺纤维化。 3）研究胞吐作用增加的假设是一种致病性 CCM疾病的基础。 4）调查MEKK3是NADPH的负调节器 氧化酶2（NOD2）和急性呼吸窘迫综合征的潜在治疗靶标。 该项目的每个项目都具有很高的创新性，并将对各自领域产生强大的影响。 此外，我们正在产生来自这些高风险/高奖励研究的新线索 其中包括基于CRISPR/CAS9和RNAi技术的功能基因组筛选。 那就是这种R35机制不仅允许简化我们的赠款申请和 管理层使我们可以更好地将精力集中在研究上，但也可以使我们有灵活性 完全有效地追求来自这些高风险/高奖励研究的新线索。 我们的往绩强烈表明了我们的准备，能力和成功购买主题 即使它们属于我们最初的意图，我们认为它们具有高影响力。

项目成果

Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3.

• DOI: 10.1126/scitranslmed.abc2499
• 发表时间: 2021-04-28
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Yuan Q;Basit A;Liang W;Qu R;Luan Y;Ren C;Li A;Xu X;Liu X;Yang C;Kuo A;Pierce R;Zhang L;Turk B;Hu X;Li F;Cui W;Li R;Huang D;Mo L;Sessa WC;Lee PJ;Kluger Y;Su B;Tang W;He J;Wu D
• 通讯作者: Wu D

Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment.

• DOI: 10.1016/j.devcel.2019.02.023
• 发表时间: 2019-04
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Chunguang Ren;Qianying Yuan;M. Braun;Xia Zhang;B. Petri;Jiasheng Zhang;Dongjoo Kim;J. Guez-Haddad;Wenzhi Xue;Weijun Pan;R. Fan;P. Kubes;Zhaoxia Sun;Y. Opatowsky;F. Polleux;E. Karatekin;Wenwen Tang;Dianqing Wu

shRNA-Induced Gene Knockdown In Vivo to Investigate Neutrophil Function.

shRNA 诱导体内基因敲低以研究中性粒细胞功能。

• DOI: 10.1007/978-1-4939-3480-5_13
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Basit,Abdul;Tang,Wenwen;Wu,Dianqing
• 通讯作者: Wu,Dianqing

Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1.

• DOI: 10.3389/fphar.2021.667361
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Han S;Zhang H;Yi M;Liu X;Maegawa GHB;Zou Y;Wang Q;Wu D;Ye Z
• 通讯作者: Ye Z

Pazopanib Is a Potential Treatment for Coronavirus-Induced Lung Injuries.

• DOI: 10.4049/jimmunol.2100968
• 发表时间: 2022-08-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Luan, Yi;Yuan, Qianying;Wang, Qijun;Compton, Susan;Wu, Dianqing;Tang, Wenwen
• 通讯作者: Tang, Wenwen