Role of COPII Vesicles in T cell immunity

COPII 囊泡在 T 细胞免疫中的作用

• 批准号: 10020752
• 负责人: Stephanie Hane Kim
• 金额: $ 2.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020752
• 关键词: Acute; Alloantigen; Amino Acid Sequence; Antiviral Response; Autoimmunity; Biological; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; CD8B1 gene; Capsid Proteins; Cell physiology; Cell secretion; Cells; Cellular Immunity; Cellular biology; Code; Congenital dyserythropoietic anemia; Data; Defect; Disease; Endoplasmic Reticulum; Exhibits; Gene Expression; Goals; Golgi Apparatus; Graft Rejection; Growth; Histocompatibility; Human; Immune; Immune response; Immunity; Immunology; Impairment; In Vitro; Infection; Inflammatory; Insulin-Dependent Diabetes Mellitus; Knock-out; Knockout Mice; Lead; Link; Lymphocyte; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mass Spectrum Analysis; Mediating; Minor; Modeling; Modernization; Mus; Mutation; Pathogenicity; Pathologic; Pathway interactions; Pattern; Phenotype; Physicians; Play; Process; Proteins; Research; Research Proposals; Rheumatoid Arthritis; Role; Scientist; Severity of illness; Stains; T-Lymphocyte; Testing; Time; Tissue Harvesting; Tissues; Training; Transport Process; Travel; Vesicle; Viral; Virus Diseases; Work; adaptive immune response; base; cell mediated immune response; clinically relevant; conditional knockout; cytokine; cytotoxic; disorder control; experimental study; graft vs host disease; graft vs leukemia effect; in vivo; in vivo Model; insight; isoimmunity; novel; paralogous gene; programs; protein complex; response; tumor

PROJECT SUMMARY / ABSTRACT T cells play an important role in protective adaptive immune responses, but also contribute to inflammatory diseases such as rheumatoid arthritis, Type I diabetes mellitus, and graft rejection. They elicit a wide range of effector activities by secreting various cytokines and cytotoxic factors that influence other immune cells and surrounding tissue. However, gaps remain in our understanding of the shared common pathways that lead up to their release. Classically, secreted proteins travel from the endoplasmic reticulum (ER) to the Golgi apparatus in vesicles generated by a group of proteins called Coat Protein Complex II (COPII). While COPII vesicles play a critical role in ER-to-Golgi transport, the processes driven by COPII vesicles in T cell functions such as effector cytokine release are unknown. The overall goal of this proposal is to study the role of COPII vesicles in T cell biology, and to examine their relevance in pathogenic and protective T cell processes in vivo. Given the fundamental role of COPII vesicles in the secretory pathway, the central hypothesis of this proposal is that the disruption of COPII vesicle formation will lead to defects in the release of specific cytokines by T cells and thus impact their biological functions. This hypothesis was formed based on preliminary data I have generated using novel T cell-specific conditional knock-out mice lacking a necessary component of the COPII coat, Sec23. The scientific aims of the proposal are: (1) to determine the impact of disruption of COPII formation on mature naïve T cell functions, and (2) to determine the mechanisms of Sec23 paralogs in T cell functions. Under the first aim, I will explore the consequences of abrogating COPII formation on T cell protective and pathogenic functions. To do this, I will use well-established in vivo models of T cell-mediated anti-viral responses and alloimmunity, as well as explore relevance to human T cells. Under the second aim, I will explore whether T cells depend on different COPII paralogs for unique functions. Humans and mice carry two Sec23 paralogs, and it is believed that they can functionally compensate for each other and are expressed in a tissue-specific manner due to evolutionary shifts in gene expression. However, my preliminary data show the surprising observation that murine T cells express both paralogs. I will assess the contribution of these two Sec23 paralogs to broad cytokine secretion patterns using modern approaches to protein quantification and begin to explore the mechanisms of COPII-mediated transport in T cells. This proposal, when completed, will provide novel and fundamental insights into T cell-mediated immunity. It will also serve as a platform to achieve my training goals in experimental immunology, and to provide me with requisite training for my long- term goals as a physician scientist.

项目总结/摘要 T细胞在保护性适应性免疫应答中发挥重要作用，但也有助于炎症反应。 疾病，如类风湿性关节炎、I型糖尿病和移植排斥。它们引发了广泛的 通过分泌影响其他免疫细胞的各种细胞因子和细胞毒性因子， 周围组织然而，在我们对导致全球化的共同途径的理解方面， 释放他们传统上，分泌的蛋白质从内质网（ER）到高尔基体 囊泡中的装置由一组称为外壳蛋白复合物II（COPII）的蛋白质产生。虽然COPII 囊泡在ER到高尔基体的转运中起关键作用，该过程由COPII囊泡在T细胞功能中驱动 例如效应细胞因子释放是未知。本提案的总体目标是研究COPII的作用 囊泡在T细胞生物学中的作用，并研究它们在体内致病性和保护性T细胞过程中的相关性。 考虑到COPII囊泡在分泌途径中的基本作用， COPII囊泡形成的破坏将导致T细胞释放特异性细胞因子的缺陷。 细胞，从而影响其生物功能。这个假设是基于我掌握的初步数据 使用缺乏COPII必需组分的新型T细胞特异性条件性敲除小鼠产生 外套，Sec 23.该提案的科学目标是：（1）确定COPII中断的影响 （2）确定Sec 23旁系同源物在T细胞中的作用机制 功能协调发展的在第一个目标下，我将探索废除COPII形成对T细胞的影响。 保护和致病功能。为此，我将使用完善的T细胞介导的体内模型， 抗病毒反应和同种异体免疫，以及探索与人类T细胞的相关性。第二个目标，我 将探索T细胞是否依赖于不同的COPII旁系同源物来实现独特的功能。人类和老鼠携带 两个Sec 23旁系同源物，并且据信它们可以在功能上相互补偿，并且表达为 由于基因表达的进化变化，不过，我的初步数据显示 令人惊讶的发现是鼠T细胞表达两种旁系同源物。我将评估这两个人的贡献 Sec 23与使用现代蛋白质定量方法的广泛细胞因子分泌模式旁系同源， 开始探索COPII介导的T细胞转运机制。这项建议完成后，将 为T细胞介导的免疫提供了新的基本见解。它还将作为一个平台， 实现我在实验免疫学方面的培训目标，并为我提供必要的培训， 作为一名医生科学家的长期目标。