Role of COPII Vesicles in T cell immunity

COPII 囊泡在 T 细胞免疫中的作用

• 批准号: 9756619
• 负责人: Stephanie Hane Kim
• 金额: $ 3.7万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756619
• 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; 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.

项目摘要/摘要 T细胞在保护性适应性免疫反应中发挥重要作用，但也有助于炎症反应。 风湿性关节炎、I型糖尿病和移植物排斥反应等疾病。它们引发了广泛的 通过分泌各种细胞因子和细胞毒因子来影响其他免疫细胞和 周围的组织。然而，在我们对共同道路的理解上仍然存在差距 为他们的获释。传统上，分泌的蛋白质从内质网(ER)进入高尔基体。 囊泡中的器官由一组称为外壳蛋白复合体II(COPII)的蛋白质产生。而COPII 小泡在内质网到高尔基体的转运中起着关键作用，这是COPII囊泡在T细胞功能中驱动的过程 例如效应器细胞因子释放是未知的。该提案的总体目标是研究COPII的作用 T细胞生物学中的小泡，并检查它们在体内致病和保护T细胞过程中的相关性。 鉴于COPII囊泡在分泌途径中的基础作用，这一提议的中心假设 COPII囊泡形成的破坏将导致T细胞释放特定细胞因子的缺陷 并因此影响它们的生物功能。这一假设是基于我所掌握的初步数据而形成的 用缺乏COPII必要成分的新型T细胞特异性条件性基因敲除小鼠产生 大衣，第23章。该提案的科学目标是：(1)确定COPII中断的影响 成熟幼稚T细胞功能的形成，以及(2)确定T细胞中Sec23类似物的机制 功能。在第一个目标下，我将探索取消COPII形成对T细胞的影响 具有保护和致病功能。为了做到这一点，我将使用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。在第二个目标下，我 将探索T细胞是否依赖于不同的COPII类似物来实现独特的功能。人类和老鼠携带 两个Sec23并列基因，认为它们在功能上可以相互补偿，并表达 由于基因表达的进化变化，以组织特有的方式。然而，我的初步数据显示 令人惊讶的是，小鼠T细胞同时表达这两种类似基因。我将评估这两个人的贡献 Sec23与广泛的细胞因子分泌模式相似，使用现代方法进行蛋白质定量和 开始探索COPII介导的T细胞转运机制。这项提案完成后，将 对T细胞介导的免疫提供新的和基本的见解。它还将作为一个平台 完成我的实验免疫学培训目标，并为我的长期免疫学提供必要的培训。 作为内科科学家的学期目标。