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

项目摘要

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.
描述(由申请人提供):我的职业目标是指导一个独立的研究实验室探索介导宿主防御和炎症的分子机制。在炎症反应期间,G蛋白偶联受体(GPCR)和先天免疫受体同时激活,并且各自可以激活不同的细胞信号。总体假设是,炎症 GPCR 信号传导与巨噬细胞 Toll 样受体 (TLR) 激活途径的许多成分相互作用并对其进行修饰,最终增强促炎转录因子核因子 kappa B (NFkB) 的激活。初步发现支持了这一点,即白三烯 B4 (LTB4) 与其 GPCR BLT1 连接可增强 NFkB 的 TLR 依赖性激活。 GPCR 和 TLR 信号传导之间存在许多潜在的相互作用,可能共同决定 NFkB 激活的状态。为了发现这种相互作用,我们提出了一种将实验与系统生物学相结合的跨学科方法,以模拟能够通过实验进行测试的整合网络。该提案的总体计划是在我最初两年的指导培训中使用 BLT1-TLR 相互作用作为模型来获取知识和技能,该模型将在独立阶段扩展到其他类别的 GPCR。为了检验我们的假设,提出了以下具体目标: K99 时期;目标 1:确定 LTB4/BLT1 信号传导(激酶、ROI 生成)对 TLR 依赖性 NFkB 激活的重要性,目标 2:检查 LTB4/BLT1 信号传导对 TLR/IL-1β 受体及其适配器表达的影响,目标 3:开发涉及 Mo TLR 响应期间 BLT1 诱导的信号传导程序的计算模型(方程)。 R00时期:目标4:基于K99时期获得的发现,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,目标5:计算模型调节NFkB激活的细胞信号网络(GPCR和TLR),以便制定可检验的假设。该提案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研究者。 公共健康相关性:我们的建议具有直接的转化重要性,因为 GPCR、TLR 和 NFkB 是治疗干预的主要目标,并且数学模型的开发可以通过使用抑制剂来阻止炎症反应以及通过添加外源性 GPCR 激动剂来增强炎症来解锁更具体的策略来治疗压倒性和免疫抑制状态。

项目成果

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C. Henrique Serezani其他文献

C. Henrique Serezani的其他文献

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{{ truncateString('C. Henrique Serezani', 18)}}的其他基金

Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
  • 批准号:
    9980677
  • 财政年份:
    2020
  • 资助金额:
    $ 11.97万
  • 项目类别:
Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice
前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强
  • 批准号:
    10337275
  • 财政年份:
    2020
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    8762864
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    10005956
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    10418725
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    9332397
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    9088490
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
Phosphatase and tensin homolog PTEN actions in polymicrobial sepsis
磷酸酶和张力蛋白同源物 PTEN 在多种微生物败血症中的作用
  • 批准号:
    10201714
  • 财政年份:
    2014
  • 资助金额:
    $ 11.97万
  • 项目类别:
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:
    8646977
  • 财政年份:
    2010
  • 资助金额:
    $ 11.97万
  • 项目类别:
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:
    8458283
  • 财政年份:
    2010
  • 资助金额:
    $ 11.97万
  • 项目类别:

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