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

• 批准号: 7953238
• 负责人: C. Henrique Serezani
• 金额: $ 11.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953238
• 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; Cytokine Receptors; Data; Development; Diabetes Mellitus; Equation; Figs - dietary; 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; public health relevance; receptor; receptor coupling; response; skills; therapeutic development; therapy development; tool; transcription factor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our proposal have direct translational importance, since GPCRs, TLRs and NFkB are major targets of therapeutic interventions and the development of mathematical models could unlock more specific strategies to treat both overwhelming as well as immunosuppressive states by employing inhibitors to block inflammatory responses, as well as by adding exogenous GPCR agonists to enhance inflammation.

职位描述(申请人提供)：我的职业目标是领导一个独立的研究实验室，探索调节宿主防御和炎症的分子机制。在炎症反应中，G蛋白偶联受体(GPCRs)和天然免疫受体同时被激活，每个受体都可以激活不同的细胞信号。总的假设是炎性GPCR信号与巨噬细胞Toll样受体(TLR)激活途径的许多组成部分相互作用并改变，最终增强促炎转录因子核因子kB(NFkB)的激活。这得到了初步发现的支持，即白三烯B4(LTB4)连接其GPCRBLT1增强了NFkB的TLR依赖的激活。GPCR和TLR信号之间有许多潜在的相互作用，可能联合决定NFkB的激活状态。为了发现这种相互作用，我们提出了一种将实验和系统生物学相结合的跨学科方法来建模能够在实验中进行测试的集成网络。这个建议的总体计划是在我最初两年的指导培训中以BLT1-TLR相互作用为模型来获取知识和技能，并将在独立阶段扩展到其他类别的GPCR。为了验证我们的假说，提出了以下具体目标：K99期；目标1：确定LTB4/BLT1信号(激酶、ROI的产生)对TLR依赖的NFkB激活的重要性，目标2：检测LTB4/BLT1信号对TLRs/IL-1β受体及其适配器表达的影响，目标3：建立计算模型(方程)，涉及BLT1在Mo TLR反应中诱导的信号程序。R00期：目的4：基于K99期的研究结果，我们希望进一步研究BLT1以外的GAI蛋白偶联受体在TLR诱导的NFkB激活中的重要性，目的5：通过计算模型来调节NFkB的激活的细胞信号网络(GPCR和TLRs)，以形成可检验的假说。这项建议将为炎症中巨噬细胞激活的协调提供新的见解，并将促进我发展成为一名独立的研究员。 公共卫生相关性：我们的建议具有直接的翻译重要性，因为GPCRs、TLRs和NFkB是治疗干预的主要目标，而数学模型的开发可以通过使用抑制剂来阻断炎症反应以及通过添加外源性GPCR激动剂来增强炎症，从而开启治疗压倒性和免疫抑制状态的更具体的策略。