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: 8884622
• 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/8884622
• 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）的参与启动一个复杂的信号级联，最终激活几个关键的转录因子，包括NF-κB。NF-κB诱导T细胞增殖和效应分化所需的一系列基因的表达。我们最近发现了“POLKADOTS信号体”，并证明了这种复杂的细胞质结构在tcr - nf -κB级联中起着至关重要的作用。我们提出的研究目的是阐明POLKADOTS信号体精确控制NF-κB活化的分子机制。这项工作将通过确定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小组的合作来完成。通过结合我们各自小组的专业知识，我们希望这项工作能够得出新的假设和结论，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。Aim 1的目标是定量定义POLKADOTS信号体中的离散功能域，以更好地定义POLKADOTS信号体如何同时控制Bcl10信号传递到NF-κB和Bcl10的蛋白水解，限制NF-κB的激活。我们在Aim 2中的研究将分析完整的、动态的微管对POLKADOTS信号体运输和聚集的贡献，以确定这种聚集过程是否是TCR信号传导到NF-κB的动力学调节机制。在Aim 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选择性蛋白水解的机制，以及更广泛地调节p62依赖性选择性自噬的机制。总之，我们期望这些数据能够产生关于信号体如何同时协调各种信号调节活动的新的机制见解。我们进一步预测，在本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一系列对人类健康重要的生物途径中的信号转导分子机制提供新的途径。