Elucidating TCR signaling mechanisms via quantitative pattern analysis

通过定量模式分析阐明 TCR 信号传导机制

• 批准号: 9060334
• 负责人: WOLFGANG LOSERT
• 金额: $ 26.54万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-02 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060334
• 关键词: Actins; Adaptor Signaling Protein; Algorithms; Antigens; Autoimmunity; Automobile Driving; Autophagocytosis; Autophagosome; Binding; Biogenesis; Biological; Biological Phenomena; Collaborations; Complex; Cytoplasmic Structures; Cytoskeleton; Data; Development; Elements; Genes; Goals; Graft Rejection; Health; Human; Image; Immune response; Kinetics; Lead; Malignant Neoplasms; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Methodology; Methods; Microscopy; Microtubule-Organizing Center; Microtubules; Molecular; NF-kappa B; Nuclear Translocation; Optics; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphorylation; Play; Process; Proteins; Proteolysis; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Structure; System; T-Cell Proliferation; T-Cell Receptor; Time; Translating; Work; analytical method; base; human disease; innovation; insight; mathematical analysis; novel; novel strategies; particle; protein distribution; transcription factor; transmission process

DESCRIPTION (provided by applicant): Engagement of the T cell receptor (TCR) initiates a complex signaling cascade that culminates in activation of several key transcription factors, including NF-κB. NF-κB induces expression of a wide array of genes required for T cell proliferation and effector differentiation. We have recently identified the "POLKADOTS signalosome," and we have demonstrated that this complex cytoplasmic structure plays an essential role in the TCR-to-NF-κB cascade. The purpose of our proposed studies is to elucidate the molecular mechanisms by which the POLKADOTS signalosome precisely controls activation of NF-κB. This work will be accomplished via collaboration between the groups of Brian Schaefer, who identified the POLKADOTS signalosome, and Wolfgang Losert, who has developed algorithms for quantitative analysis of patterns of protein distribution. By combining the expertise of our respective groups, we expect this work to lead to new hypotheses and conclusions regarding how changes in protein distribution are mechanistically connected to the signaling function of the POLKADOTS signalosome. We will achieve these goals through three Aims: The goal of Aim 1 is to quantitatively define discrete functional domains within POLKADOTS signalosome, to better define how the POLKADOTS signalosome simultaneously controls both Bcl10 signal transmission to NF-κB and proteolysis of Bcl10, limiting NF-κB activation. Our studies in Aim 2 will analyze the contribution of intact, dynamic microtubules to the transport and aggregation of POLKADOTS signalosomes, to determine whether this aggregation process is a mechanism of kinetic regulation of TCR signaling to NF-κB. In Aim 3, we will determine how actin cytoskeletal dynamics regulate selective autophagy of Bcl10, revealing mechanisms controlling the selective proteolysis of Bcl10, and, more generally, mechanisms regulating p62-dependent selective autophagy. Together, we expect these data to yield new mechanistic insights regarding how signalosomes simultaneously coordinate diverse signal regulatory activities. We furthermore predict the innovative analytical methods developed in the course of this research could be readily translated to other signaling systems. Our work will thus suggest new avenues for exploring molecular mechanisms of signal transduction in a wide array of biological pathways important to human health.

描述(由申请人提供)：T细胞受体(TCR)的参与启动了一个复杂的信号级联反应，最终激活了几个关键的转录因子，包括核因子-κB。核因子-κB诱导T细胞增殖和效应器分化所需的广泛基因的表达。我们最近发现了“POLKADOTS信号小体”，并证明了这种复杂的细胞质结构在TcR到NF-κB级联反应中发挥着重要作用。我们提出的研究的目的是阐明POLKADOTS信号体精确控制NF-κB激活的分子机制。这项工作将通过鉴定POLKADOTS信号体的Brian Schaefer和开发了定量分析蛋白质分布模式的算法的Wolfgang Losert的团队合作完成。通过结合我们各自小组的专业知识，我们预计这项工作将导致新的假设和结论，即蛋白质分布的变化如何与POLKADOTS信号体的信号功能机械地联系在一起。我们将通过三个目标来实现这些目标：目标1的目标是定量地定义POLKADOTS信号小体中的离散功能结构域，以更好地定义POLKADOTS信号小体如何同时控制Bcl10向NF-κB的信号传递和Bcl10的蛋白降解，从而限制NF-κB的激活。我们在目标2中的研究将分析完整的、动态的微管对POLKADOTS信号小体的运输和聚集的贡献，以确定这种聚集过程是否是TcR信号对NF-κB的动力学调节机制。在目标3中，我们将确定肌动蛋白细胞骨架动力学如何调节bcl10的选择性自噬，揭示控制bcl10选择性蛋白分解的机制，以及更广泛地说，调控依赖p62的选择性自噬的机制。总之，我们希望这些数据能够产生关于信号体如何同时协调不同的信号调节活动的新的机械性见解。我们还预测，在这项研究过程中开发的创新分析方法可以很容易地转化为其他信号系统。因此，我们的工作将为探索广泛的对人类健康重要的生物途径中的信号转导的分子机制提供新的途径。