Regulation of CARD11 by a kinesin-like protein, GAKIN

驱动蛋白样蛋白 GAKIN 对 CARD11 的调节

基本信息

  • 批准号:
    7406429
  • 负责人:
  • 金额:
    $ 3.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-10-01 至 2010-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The ability of the immune system to defend against pathogens critically depends on the ability of T cells to recognize foreign antigens and respond appropriately. Upon encountering antigen, the T cell receptor (TCR) triggers intracellular signaling pathways that activate of a set of transcription factors to induce new programs of gene expression. The activation of the transcription factor NF-kB by TCR signaling is required for normal antigen-induced T cell proliferation, survival and effector function. CARD11 is a multi-domain adapter protein that is required for TCR-mediated activation of NF-kB, but its mechanisms of action are incompletely understood. To isolate CARD11 signaling cofactors, a novel expression-cloning screen was conducted to isolate modulators of CARD11 activity. From this screen, a kinesin-like protein, GAKIN, was identified as an inhibitor of CARD11, and preliminary studies suggest that GAKIN functions as an inhibitor of TCR signaling to NF-kB. The goal of the proposed research is to investigate how GAKIN functions in this important signaling pathway. The experiments are designed to test the overall hypothesis that GAKIN inhibits TCR signaling to NF-kB by binding CARD11 directly and transporting it away from the immunological synapse. The hypothesis will be tested with three specific aims. First, using GAKIN-deficient and GAKIN-overexpressing T cell lines, several steps in the TCR-to-NF-kB pathway will be assayed to determine the step at which GAKIN acts. Second, the domains of GAKIN that are required for its inhibitory activity will be determined using an RNA interference-rescue assay. Third, binding assays and T cell:APC (antigen presenting cell) imaging assays will be used to demonstrate whether or not GAKIN binds CARD11directly and influences the kinetics or extent of CARD11 recruitment to the immunological synapse. The results of these studies should expand our understanding of the molecular machinery that controls T cell activation in the adaptive immune response. In addition, this research may offer insight into the dysregulated signaling that is observed in aging T cells, which can contribute to ineffective immune responses and increased susceptibility to pathogens. Immune cell signaling defects are commonly seen in aged humans and this results in impaired responses to pathogens. The results of the proposed research have the potential to advance the understanding of the molecular machinery that immune cells use to mount an effective response. The results may also provide a target for the development of novel therapeutics that could enhance immune responses that are dysregulated in aging.
描述(由申请方提供):免疫系统防御病原体的能力主要取决于T细胞识别外源抗原并适当应答的能力。当遇到抗原时,T细胞受体(TCR)触发细胞内信号传导途径,其激活一组转录因子以诱导新的基因表达程序。通过TCR信号传导激活转录因子NF-kB是正常抗原诱导的T细胞增殖、存活和效应子功能所需的。CARD 11是TCR介导的NF-κ B活化所需的多结构域衔接蛋白,但其作用机制尚不完全清楚。为了分离CARD 11信号传导辅因子,进行新的表达克隆筛选以分离CARD 11活性的调节剂。从该筛选中,驱动蛋白样蛋白GAKIN被鉴定为CARD 11的抑制剂,并且初步研究表明GAKIN作为TCR信号传导至NF-κ B的抑制剂起作用。这项研究的目的是研究GAKIN如何在这一重要的信号通路中发挥作用。这些实验旨在测试GAKIN通过直接结合CARD 11并将其转运远离免疫突触来抑制TCR向NF-κ B的信号传导的总体假设。将以三个具体目标来检验这一假设。首先,使用GAKIN缺陷型和GAKIN过表达型T细胞系,分析TCR-至-NF-kB途径中的几个步骤以确定GAKIN起作用的步骤。其次,将使用RNA干扰拯救测定法确定GAKIN抑制活性所需的结构域。第三,结合试验和T细胞:APC(抗原呈递细胞)成像试验将用于证明GAKIN是否直接结合CARD 11并影响CARD 11募集至免疫突触的动力学或程度。这些研究的结果应该扩大我们对在适应性免疫反应中控制T细胞活化的分子机制的理解。此外,这项研究可以深入了解在衰老T细胞中观察到的失调信号,这可能导致无效的免疫反应和对病原体的易感性增加。免疫细胞信号传导缺陷在老年人中常见,这导致对病原体的反应受损。拟议研究的结果有可能促进对免疫细胞用于建立有效反应的分子机制的理解。这些结果也可能为开发新的治疗方法提供目标,这些治疗方法可以增强在衰老中失调的免疫反应。

项目成果

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REBECCA L LAMASON其他文献

REBECCA L LAMASON的其他文献

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{{ truncateString('REBECCA L LAMASON', 18)}}的其他基金

Microbial Control of Host Intercellular Communication
宿主细胞间通讯的微生物控制
  • 批准号:
    10363966
  • 财政年份:
    2022
  • 资助金额:
    $ 3.46万
  • 项目类别:
Microbial Control of Host Intercellular Communication
宿主细胞间通讯的微生物控制
  • 批准号:
    10661500
  • 财政年份:
    2022
  • 资助金额:
    $ 3.46万
  • 项目类别:
Mechanisms of SFG Rickettsia-Host Interactions
SFG 立克次体与宿主相互作用的机制
  • 批准号:
    10293664
  • 财政年份:
    2021
  • 资助金额:
    $ 3.46万
  • 项目类别:
Mechanisms of SFG Rickettsia-Host Interactions
SFG 立克次体与宿主相互作用的机制
  • 批准号:
    10468216
  • 财政年份:
    2021
  • 资助金额:
    $ 3.46万
  • 项目类别:
Mechanisms of SFG Rickettsia-Host Interactions
SFG 立克次体与宿主相互作用的机制
  • 批准号:
    10651764
  • 财政年份:
    2021
  • 资助金额:
    $ 3.46万
  • 项目类别:
Elucidating how intracellular bacterial pathogens hijack host intercellular communication to promote spread
阐明细胞内细菌病原体如何劫持宿主细胞间通讯以促进传播
  • 批准号:
    9132279
  • 财政年份:
    2015
  • 资助金额:
    $ 3.46万
  • 项目类别:
Elucidating how intracellular bacterial pathogens hijack host intercellular communication to promote spread
阐明细胞内细菌病原体如何劫持宿主细胞间通讯以促进传播
  • 批准号:
    9529899
  • 财政年份:
    2015
  • 资助金额:
    $ 3.46万
  • 项目类别:
Regulation of CARD11 by a kinesin-like protein, GAKIN
驱动蛋白样蛋白 GAKIN 对 CARD11 的调节
  • 批准号:
    7671431
  • 财政年份:
    2007
  • 资助金额:
    $ 3.46万
  • 项目类别:
Regulation of CARD11 by a kinesin-like protein, GAKIN
驱动蛋白样蛋白 GAKIN 对 CARD11 的调节
  • 批准号:
    7505435
  • 财政年份:
    2007
  • 资助金额:
    $ 3.46万
  • 项目类别:

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