Regulation of NF-kB by TCR and costimulatory signaling

TCR 和共刺激信号对 NF-kB 的调节

• 批准号: 8381804
• 负责人: Joel L Pomerantz
• 金额: $ 31.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381804
• 关键词: Antigen Receptors; Antigens; Autoimmunity; Binding; CD28 gene; Calcium Signaling; Cell physiology; Cells; Coiled-Coil Domain; Collection; Complementary DNA; Complex; Cues; Cytoplasmic Tail; Engineering; Enhancers; Goals; Human; Immune; Immune System Diseases; Immunologic Surveillance; Kinesin; Knock-in Mouse; Link; MAP3K7 gene; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; NF-kappa B; Open Reading Frames; Pathway interactions; Phase; Phosphorylation; Play; Proteins; RNA Interference; Recruitment Activity; Regulation; Role; Screening procedure; Signal Pathway; Signal Transduction; Signaling Molecule; Spleen; Stimulus; Structure; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TRAF6 gene; Tail; Technology; Testing; Work; anergy; arm; base; cDNA Library; caspase-8; domain mapping; expression cloning; genome wide association study; immunological synapse; immunological synapse formation; inhibitor/antagonist; insight; interest; mouse model; mutant; novel; programs; reconstitution; response; scaffold; therapy design; tool; transcription factor

This Project will contribute to the overall goals of the Program by investigating the arm of TCR signaling that activates NF-KB, a transcription factor that is required for antigen-induced T cell proliferation and activation. The study of TCR signaling to NF-KB offers several opportunities to expand our understanding of how a T cell interprets antigenic inputs. First, the mechanistic understanding of how the TCR activates NF-KB is far from complete. Critical components of this pathway remain undiscovered and it is likely that new players in this pathway will also play important roles in other arms of TCR signaling studied in the Program. In AIM 1, we will use a novel expression cloning strategy to identify enhancers and suppressors of TCR signaling to NF-KB. Second, maximal TCR-mediated NF-KB activation requires both TCR engagement by MHC plus antigen (signal 1) and costimulatory signals (signal 2). In AIM 2, we will test the hypothesis that the CARD11- GADS interaction is required for CD28-mediated costimulatory signaling to NF-KB. Third, while it is clear that molecules that signal from the TCR to NF-KB are recruited to the immunological synapse (IS) in a dynamic, regulated manner, it is unclear how and why this is precisely accomplished. In AIM 3, we will investigate how NF-KB signaling intermediates are recruited to the immunological synapse. This project will benefit from synergy with other projects in the Program. AIM 1 will use Core C and should yield novel components or modulators of TCR signaling pathways that can be studied in Projects 1, 2, 3, and 4 for roles in TCR clustering, Immunological Synapse (IS) formation and regulation, Sprouty!-mediated regulation, and calcium signaling, respectively. AIM 2 may offer molecular insight into how a T cell makes the cellular choice of activation or anergy, and will apply a mouse model and the expertise of J. Powell (Project 3). AIM 3 will use Core B and technology developed by A. Kupfer (Project 2) and will contribute to the understanding of IS formation and structure during T cell activation. Our results should add to the understanding of how the molecular machinery of immune cells can recognize and interpret environmental cues, including pathogenic and nonpathogenic stimuli, and respond appropriately. Since the inappropriate response to stimuli can result in ineffective immune surveillance, autoimmunity, or cancer, our results may yield molecular targets for new therapies designed to treat diseases of the immune system.

该项目将通过调查TCR信号的手臂来促进该计划的整体目标 激活NF-KB，这是抗原诱导的T细胞增殖和激活所需的转录因子。 对NF-KB的TCR信号的研究提供了一些机会，以扩大我们对T的理解 细胞解释抗原输入。首先，对TCR如何激活NF-KB的机械理解远 从完成。该途径的关键组成部分仍未被发现，很可能是 该途径还将在该程序中研究的TCR信号的其他臂中扮演重要角色。在AIM 1中， 我们将使用一种新颖的表达克隆策略来识别TCR信号的增强子和抑制器 NF-KB。其次，最大的TCR介导的NF-KB激活需要MHC Plus的TCR参与 抗原（信号1）和共刺激信号（信号2）。在AIM 2中，我们将测试Card11-的假设 GADS相互作用是CD28介导的对NF-KB的共刺激信号传导所必需的。第三，虽然很明显 从TCR到NF-KB信号的分子在动态中募集到免疫突触（IS） 受监管的方式，目前尚不清楚如何以及为什么要完成这项工作。在AIM 3中，我们将调查如何 NF-KB信号传导中间体被招募到免疫突触。这个项目将从 与该计划中的其他项目协同作用。 AIM 1将使用核心C，并应产生新颖的组件或 在项目1、2、3和4中可以研究的TCR信号通路的调节器 聚类，免疫突触（IS）形成和调节，发芽！介导的调节和钙 信号分别。 AIM 2可以提供分子洞察T细胞如何使细胞选择的细胞选择 激活或反对意见，并将应用鼠标模型和J. Powell的专业知识（项目3）。 AIM 3将使用 核心B和A. Kupfer（项目2）开发的技术，将有助于理解IS T细胞激活过程中的形成和结构。我们的结果应该增加对如何 免疫细胞的分子机制可以识别和解释环境线索，包括致病性 和非致病性刺激，并做出适当的反应。由于对刺激的不适当反应会导致 在无效的免疫监测，自身免疫性或癌症中，我们的结果可能会产生新的分子靶标 旨在治疗免疫系统疾病的疗法。