Non-linear transduction of TCR signals leading to Ras activation

TCR 信号的非线性转导导致 Ras 激活

基本信息

  • 批准号:
    8503586
  • 负责人:
  • 金额:
    $ 69.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

Efficient thymocyte selection is critical to generate T lymphocytes with a very broad spectrum of specific T cell receptors (TCR) that recognize foreign antigens, while avoiding development of autoimmunity. The exact molecular mechanisms underlying thymocyte positive versus negative selection are not know, but different patterns of Ras-MAP kinase (MAPK) activation have long been postulated to be involved. MAPK are tunable signaling molecules that lie downstream of active Ras and that regulate gene expression. We hypothesize that the choice of Ras Guanine nucleotide Exchange Factors usage, namely RasGRP or SOS + RasGRP, governs distinct Ras activation characteristics and thymocyte selection. This project will focus on understanding the characteristics of Ras-MAPK signaling by RasGRP1 and SOS1 and how this affects thymocyte fate decisions by combining the biophysical, computational, and cellular-biochemical expertise of the Kuriyan (UCB), Groves (UCB), Chakraborty (MIT), and Roose (UCSF) labs. Combination of: 1) purified recombinant proteins; 2) a model two dimensional lipid bilayer system containing defined quantities of recombinant proteins; 3) computational modeling; and 4) model systems of the Jurkat T cell, DT40 B cell, and mutant cell lines and mouse model studies provide an unique approach that has not been taken previously. The overall goal of project #2 is to understand the distinct characteristics of Ras-MAPK activation via RasGRP1 or SOS1, downstream of LAT, and how these signaling events impact thymocyte selection. In Aim 1, we will characterize RasGRP1 RasGEF function utilizing the three scientific disciplines in iterative approaches. In Aim 2, we will define the requirement of allosteric regulation of the RasGEF SOS1. In Aim 3. we will define the molecular basis of RasGRP1-SOS1 synergy. In Aim 4, we will Characterize the role of LAT in digital Ras-MAPK signaling. In Aim 5. we will define the role of SOS-mediated Ras activation in thymocyte selection. Understanding the specific nature of Ras activation and the downstream activation of the ERK, P38, and JNK MAPK will be the endpoint goals for this project; specifically we will focus on the role of the RasGEF characteristics of RasGRP1 and SOS1 as well as on phospho-LAT, which could serve as a point of bifurcation between analog and digital Ras signaling. We expect that we will gain insights from both concurrence and contradiction between the three disciplines. By building step-wise to increasingly complex models we aim to understand the molecular mechanism of selective Ras-MAPK activation patterns and how these impact thymocyte selection.
高效的胸腺细胞选择对于产生具有广谱特异性T细胞受体(TCR)的T淋巴细胞至关重要,这些T淋巴细胞可以识别外来抗原,同时避免自身免疫的发展。胸腺细胞阳性选择与阴性选择的确切分子机制尚不清楚,但长期以来一直假设涉及不同模式的Ras-MAP激酶(MAPK)激活。MAPK是可调节的信号分子,位于活性Ras的下游,调节基因表达。我们假设选择Ras鸟嘌呤核苷酸交换因子的使用,即RasGRP或SOS +

项目成果

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JEROEN ROOSE其他文献

JEROEN ROOSE的其他文献

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{{ truncateString('JEROEN ROOSE', 18)}}的其他基金

Project 2
项目2
  • 批准号:
    10159451
  • 财政年份:
    2020
  • 资助金额:
    $ 69.47万
  • 项目类别:
Project 2
项目2
  • 批准号:
    10208652
  • 财政年份:
    2020
  • 资助金额:
    $ 69.47万
  • 项目类别:
Molecular understanding of cytokine-Ras signals in leukemic bone marrow
白血病骨髓中细胞因子-Ras 信号的分子理解
  • 批准号:
    9296107
  • 财政年份:
    2015
  • 资助金额:
    $ 69.47万
  • 项目类别:
Molecular understanding of cytokine-Ras signals in leukemic bone marrow
白血病骨髓中细胞因子-Ras 信号的分子理解
  • 批准号:
    9103012
  • 财政年份:
    2015
  • 资助金额:
    $ 69.47万
  • 项目类别:
Molecular understanding of leukemic bone marrow cytokine-Ras signals and metabolic dependence
白血病骨髓细胞因子-Ras 信号和代谢依赖性的分子理解
  • 批准号:
    10545014
  • 财政年份:
    2015
  • 资助金额:
    $ 69.47万
  • 项目类别:
Molecular understanding of leukemic bone marrow cytokine-Ras signals and metabolic dependence
白血病骨髓细胞因子-Ras 信号和代谢依赖性的分子理解
  • 批准号:
    10363571
  • 财政年份:
    2015
  • 资助金额:
    $ 69.47万
  • 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
  • 批准号:
    10396864
  • 财政年份:
    2014
  • 资助金额:
    $ 69.47万
  • 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
  • 批准号:
    8696061
  • 财政年份:
    2014
  • 资助金额:
    $ 69.47万
  • 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
  • 批准号:
    9237188
  • 财政年份:
    2014
  • 资助金额:
    $ 69.47万
  • 项目类别:
Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants
具有信号变异的自身免疫 T 辅助细胞失去内在控制
  • 批准号:
    8810642
  • 财政年份:
    2014
  • 资助金额:
    $ 69.47万
  • 项目类别:

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