Characterizing the nuclear pore complex-T cell receptor connection

表征核孔复合体-T 细胞受体连接

• 批准号: 10304176
• 负责人: Maximiliano A DAngelo
• 金额: $ 65.36万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-16 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304176
• 关键词: Active Sites; Adaptor Signaling Protein; Amino Acids; Antibody Formation; Autoimmune Diseases; B-Lymphocytes; Biological Response Modifiers; C-terminal; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Caveolins; Cell Nucleus; Cell Survival; Cell membrane; Cell physiology; Cells; Cytoplasm; Data; Development; Dimerization; Ensure; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Immune; Immune response; Immune system; Immunity; Immunotherapy; Infection; Inflammation; Insulin; Integral Membrane Protein; LCP2 gene; Ligation; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Nuclear; Nuclear Envelope; Nuclear Pore; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Pathology; Pathway interactions; Phosphorylation; Play; Process; Proteins; RAN GTPase Activating Protein 1; Receptor Activation; Receptor Signaling; Regulation; Regulator Genes; Research Project Grants; Role; STAT3 gene; Signal Transduction; Surface; T cell regulation; T cell therapy; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Transactivation; Transcriptional Activation; Tumor stage; Work; adaptive immune response; caveolin-2; chronic infection; insight; macrophage; novel; nucleocytoplasmic transport; pathogen; recruit; response; scaffold; transcription factor; transmission process; tumor growth

PROJECT SUMMARY Nuclear pore complexes (NPCs) are large multiprotein channels that connect the nucleus with the cytoplasm. In addition to their role in controlling nucleocytoplasmic transport, NPCs play key roles in gene expression regulation. The molecular mechanisms employed by NPCs and its components (nucleoporins) to regulate gene expression in mammalian cells are still poorly understood. Recent evidence indicates that NPCs have important functions in the immune system. CD4+ T lymphocytes are central players of the adaptive immune response. These cells assist B cells with antibody production, help CD8+ T lymphocytes to clear infections and to control tumor growth, stimulate macrophage activity, recruit immune cells to sites of active infection and inflammation, and exert regulatory roles that are essential to control the extent of the immune response. CD4+ T lymphocytes activate through the stimulation of their T cell receptor (TCR) at the plasma membrane. TCR engagement results in the initiation of the TCR signaling cascade that regulates T cell activation, proliferation, function and survival. We recently identified that the nuclear pore complex component Nup210 has a critical role in the transmission of TCR signals, and in the activation and survival of CD4+ T cells. We found that Nup210 regulates T cell activation by modulating gene expression in response to TCR stimulation. Our findings suggest that a coordinated activity between the plasma membrane and the nuclear envelope is required for the proper transmission of TCR signals and the efficient expression of TCR-induced genes. In this proposal we aim to establish how the TCR stimulation signal is communicated from the plasma membrane to Nup210 at NPCs (Aim 1), to dissect how Nup210 regulates the transcriptional activity NFAT and STAT transcription factors during TCR signaling (Aim 2), and to uncover the role of the Caveolin 2 protein in Nup210-regulation of TCR-induced gene expression (Aim 3). Besides offering novel insights into the mechanisms of gene expression modulation by nucleoporins, we expect our work will result in the characterization of a new mechanism of regulation of T cell function that could potentially be exploited to modulate T cell activity in immune-based therapies.

项目概要 核孔复合体（NPC）是连接细胞核与细胞质的大型多蛋白通道。在 除了控制核细胞质运输之外，NPC 在基因表达中也发挥着关键作用 规定。 NPC及其成分（核孔蛋白）调节基因的分子机制 哺乳动物细胞中的表达仍知之甚少。最近的证据表明 NPC 具有重要作用 在免疫系统中发挥作用。 CD4+ T 淋巴细胞是适应性免疫反应的核心参与者。 这些细胞协助 B 细胞产生抗体，帮助 CD8+ T 淋巴细胞清除感染并控制 肿瘤生长，刺激巨噬细胞活性，将免疫细胞募集到活跃感染和炎症部位， 并发挥对控制免疫反应程度至关重要的调节作用。 CD4+T淋巴细胞 通过刺激质膜上的 T 细胞受体 (TCR) 来激活。 TCR 参与结果 TCR 信号级联的启动，调节 T 细胞的激活、增殖、功能和存活。 我们最近发现核孔复合体成分Nup210在传输中具有关键作用 TCR 信号以及 CD4+ T 细胞的激活和存活。我们发现Nup210调节T细胞 通过响应 TCR 刺激调节基因表达来激活。我们的研究结果表明 质膜和核膜之间的协调活动是适当的 TCR信号的传递和TCR诱导基因的有效表达。在本提案中，我们的目标是 建立 TCR 刺激信号如何从质膜传递到 NPC 处的 Nup210（目标 1）、剖析Nup210在TCR过程中如何调节转录活性NFAT和STAT转录因子 信号传导（目标 2），并揭示 Caveolin 2 蛋白在 Nup210 调节 TCR 诱导基因中的作用 表达（目标 3）。除了提供关于基因表达调节机制的新见解 核孔蛋白，我们预计我们的工作将导致 T 细胞调节新机制的表征 可能会被用来调节基于免疫的疗法中的 T 细胞活性。