Regulation of Toll-like receptor-induced NFkB activation by Gai-coupled receptors

Gai 偶联受体对 Toll 样受体诱导的 NFkB 激活的调节

基本信息

批准号：
8646977
负责人：
C. Henrique Serezani
金额：
$ 23.28万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646977
关键词：
Adaptor Signaling Protein Affect Affinity Agonist Arachidonic Acids Architecture Atherosclerosis Behavior Binding Biology Cell model Chronic Chronic Disease Chronic Obstructive Airway Disease Computer Simulation Coupled Cytokine Receptors Data Development Diabetes Mellitus Equation Fostering Foundations G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Generations Goals Health Host Defense Human Immunologic Receptors Immunosuppressive Agents Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knowledge LTB4R gene Laboratory Research Leukocytes Leukotriene B4 Leukotrienes Ligands Ligation Lipids Macrophage Activation Mediating Mediator of activation protein Mentors Modeling Molecular Myelogenous NF-kappa B Nature Nuclear Oxygen Pathogenesis Pathway interactions Phase Phosphotransferases Play Production Proteins Receptor Activation Receptor Signaling Regulation Research Research Personnel Role STAT1 protein Signal Transduction Solid Suggestion System Systems Biology Testing Therapeutic Intervention Toll-like receptors Training autocrine base career cytokine inhibitor/antagonist insight interdisciplinary approach lipid mediator macrophage mathematical model novel paracrine pathogen programs receptor receptor coupling response skills therapeutic development therapy development tool transcription factor

Adaptor Signaling Protein Affect Affinity Agonist Arachidonic Acids Architecture Atherosclerosis Behavior Binding Biology Cell model Chronic Chronic Disease Chronic Obstructive Airway Disease Computer Simulation Coupled Cytokine Receptors Data Development Diabetes Mellitus Equation Fostering Foundations G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Generations Goals Health Host Defense Human Immunologic Receptors Immunosuppressive Agents Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knowledge LTB4R gene Laboratory Research Leukocytes Leukotriene B4 Leukotrienes Ligands Ligation Lipids Macrophage Activation Mediating Mediator of activation protein Mentors Modeling Molecular Myelogenous NF-kappa B Nature Nuclear Oxygen Pathogenesis Pathway interactions Phase Phosphotransferases Play Production Proteins Receptor Activation Receptor Signaling Regulation Research Research Personnel Role STAT1 protein Signal Transduction Solid Suggestion System Systems Biology Testing Therapeutic Intervention Toll-like receptors Training autocrine base career cytokine inhibitor/antagonist insight interdisciplinary approach lipid mediator macrophage mathematical model novel paracrine pathogen programs receptor receptor coupling response skills therapeutic development therapy development tool transcription factor

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项目摘要

My career goal is to direct an independent research laboratory exploring the molecular mechanisms mediating host defense and inflammation. During inflammatory responses, both G protein-coupled (GPCRs) and innate immune receptors are activated simultaneously, and each can activate diverse cellular signals. The overall hypothesis is that inflammatory GPCR signaling interacts with and modifies many components of the macrophage Toll-like receptor (TLR) activation pathway, ultimately enhancing activation of the pro-inflammatory transcription factor nuclear factor kappa B (NFkB). This is supported by the preliminary finding that leukotriene B4 (LTB4) ligation of its GPCR BLT1 enhances the TLR- dependent activation of NFkB. There are many potential interactions between GPCR and TLR signaling that might combinatorially determine the state of NFkB activation. To discover such interactions, we propose an interdisciplinary approach combining experimentation with systems biology to model integrative networks that are capable of being tested experimentally.The general plan of this proposal is to acquire knowledge and skills during my initial two years of mentored training using BLT1-TLR interactions as a model, which will be extended to other classes of GPCRs during the independent phase. To test our hypothesis, the following Specific Aims are proposed: K99 period; Aim 1: Determine the importance of LTB4/BLT1 signaling (kinases, ROI generation) to TLR-dependent NFkB activation, Aim 2: Examine the effects of LTB4/BLT1 signaling on the expression of TLRs/IL-1beta receptors and their adaptors, Aim 3: Develop computational models (equations) involving the signaling programs induced by BLT1 during Mo TLR responses. R00 period:Aim 4: Based on the findings obtained in the K99 period, we want to further investigate the importance of Gai protein-coupled receptors other than BLT1 in TLR-induced NFkB activation, Aim 5: Computationally model cellular signaling networks (GPCR and TLRs) that regulate NFkB activation in order to formulate testable hypotheses. This proposal will provide new insights into the coordination of macrophage activation in inflammation, and will foster my development into an independent investigator.

我的职业目标是指导一个独立的研究实验室探索分子机制调解宿主防御和炎症。在炎症反应期间，G蛋白耦合均为G蛋白（GPCR）和先天免疫受体同时激活，每个受体都可以激活多样细胞信号。总体假设是炎症GPCR信号与巨噬细胞收费受体（TLR）活化途径的许多成分，最终增强促炎性转录因子核因子Kappa B（NFKB）的激活。这是支持的通过初步发现，白细胞B4（LTB4）的GPCR BLT1结扎增强了TLR- NFKB的依赖激活。 GPCR和TLR信号传导之间存在许多潜在的相互作用这可能会结合确定NFKB激活的状态。为了发现这种互动，我们提出一种将实验与系统生物学结合的跨学科方法来建模能够经过实验测试的集成网络。该提案的一般计划是在我使用BLT1-TLR的最初两年的指导培训中获得知识和技能作为模型的交互作用，该模型将扩展到独立期间其他类别的GPCR 阶段。为了检验我们的假设，提出了以下特定目的：K99时期；目标1：确定 LTB4/BLT1信号传导（激酶，ROI生成）与TLR依赖性NFKB激活的重要性，目标2：检查LTB4/BLT1信号传导对TLRS/IL-1BETA受体表达的影响他们的适配器，目标3：开发涉及信号程序的计算模型（方程）在Mo TLR响应过程中由BLT1诱导。 R00时期：目标4：基于在 K99时期，我们希望进一步研究GAI蛋白偶联受体的重要性 TLR诱导的NFKB激活中的BLT1，AIM 5：计算模型的细胞信号网络（GPCR和TLR）调节NFKB激活以制定可检验的假设。这提案将为炎症中巨噬细胞激活的协调提供新的见解，将把我的发展促进独立研究者。