COPII dependent regulation of T cell alloimmunity

T 细胞同种免疫的 COPII 依赖性调节

• 批准号: 10411935
• 负责人: PAVAN REDDY
• 金额: $ 58.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411935
• 关键词: Address; Alloantigen; Allogenic; Autoimmunity; Biological Models; Biology; Capsid Proteins; Cell physiology; Cells; Cellular Metabolic Process; Data; Defect; Development; Endoplasmic Reticulum; Future; Genetic; Genetic Diseases; Genetic Transcription; Genetic Translation; Golgi Apparatus; Hematological Disease; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hereditary Disease; Human; Immune; Immunity; In Vitro; Inherited; Institutional Review Boards; Knowledge; Lead; Lipids; Location; Mammals; Mediating; Metabolic; Metabolism; Methods; Molecular; Molecular Genetics; Molecular Target; Mus; Mutate; Mutation; Organ Transplantation; Outcome; Pathogenicity; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Process; Proteins; Research Personnel; Role; Sampling; Solid; Surgical sutures; T cell regulation; T-Cell Development; T-Lymphocyte; Testing; Transgenic Mice; Translations; Vesicle; adaptive immune response; allograft rejection; cohort; cytokine; extracellular; graft vs host disease; graft vs leukemia effect; human disease; human model; in vivo; insight; isoimmunity; mouse model; new therapeutic target; novel; novel strategies; paralogous gene; protein complex; rare genetic disorder; response; secretory protein; side effect; tool; transcription factor; type II Congenital dyserythropoietic anemia

ABSTRACT T cells play a central role in adaptive immune responses. They contribute to protective as well as pathogenic processes, such as graft versus leukemia (GVL) and graft versus host disease (GVHD) respectively, after allogeneic hematopoietic cell (allo-HCT). The molecular mechanisms underpinning the T cell alloimmunity are not well-understood. Identification of novel molecular targets in alloreactive T cells could lead to better harnessing of allo-HCT, a potent therapy against many hematological and inherited diseases. Naïve T cells upon activation by allo-antigens undergo metabolic reprogramming, upregulate transcription and translation. Following translation from mRNA, many cellular proteins egress from the endoplasmic reticulum (ER) to Golgi bodies (ER to Golgi pathway) for appropriate post-translational modifications prior to their transport to final intracellular location or extracellular secretion. ER to Golgi transport is mediated by the conserved Coat Protein Complex II (COPII) vesicles. COPII vesicles are made of heterodimers of proteins, critical amongst which are the SEC23 proteins7. The role of sec23 dependent COPII mediated ER to Golgi transport in T cell immunity is unknown. This proposal will address the above knowledge gap. As preliminary data, we have generated several types of novel SEC23 transgenic mice, have an IRB approved access to rare Sec23b mutated genetic disease patient and healthy human samples for complementary murine and human studies to test the central hypothesis that the disruption of COPII by Sec23 mutation will reduce T-cell alloimmunity in vitro and in vivo. The Specific Aims (SA) are: SA 1: To determine the impact of disruption of SEC23B-dependent COPII pathway in conventional donor T cells (Tcons) on outcomes after experimental allogeneic HCT SA 2: To determine the molecular and genetic mechanisms of SEC23 dependent COPII vesicles in regulation of T cell functions. Thus our thus proposal explores a heretofore unstudied pathway, role of SEC23 dependent COPII vesicles in immunity and represents a new direction in understanding the biology, and in identification of SEC23 as a novel therapeutic target to mitigate T cell alloreactive responses after allo-HCT. It is grounded in novel preliminary data, will apply state of the art methods, utilize synergistic and complementary murine and human model systems, and is supported by co-investigators with requisite expertise. If successful, will provide fundamental mechanistic insights into T cell allo-immunity with direct implications for allo-HCT and solid organ allo-graft rejection, and may also have broad implications for autoimmunity, infectious immunity.

摘要 T细胞在获得性免疫反应中发挥核心作用。它们既有助于保护，也有助于致病 分别为移植物抗白血病(GVL)和移植物抗宿主病(GVHD) 异基因造血细胞(allo-HCT)。T细胞同种免疫的分子机制 都没有被很好地理解。在同种异体反应性T细胞中识别新的分子靶点可能导致更好的 利用allo-HCT，一种治疗许多血液病和遗传性疾病的有效疗法。幼稚T细胞 一旦被同种抗原激活，就会经历代谢重新编程，上调转录和翻译。 在从mRNA翻译后，许多细胞蛋白从内质网(ER)出口到 高尔基体(内质网到高尔基体通路)的翻译后修饰 最终的细胞内位置或细胞外分泌物。内质网到高尔基体的转运是由保守的Coat介导的 蛋白质复合体II(COPII)囊泡。COPII囊泡是由蛋白质的异二聚体组成的，在 它们是SEC23蛋白7。Sec23依赖的COPII介导的内质网对T细胞高尔基体转运的作用 豁免权是未知的。这项提议将解决上述知识差距。作为初步数据，我们有 产生了几种新型的SEC23转基因小鼠，获得了IRB批准的罕见的Sec23b突变 遗传病患者和健康人样本用于互补的小鼠和人体研究，以测试 中心性假设：Sec23突变破坏COPII会降低T细胞同种异体免疫。 在活体内。具体目标(SA)包括： SA 1：确定SEC23B依赖的COPII通路中断对常规供者T细胞的影响 细胞(Tcons)对实验性同种异体血细胞移植结局的影响 SA_2：确定SEC23依赖的COPII囊泡调控的分子和遗传机制 T细胞功能。 因此，我们的建议探索了一条迄今未被研究的途径，即依赖于SEC23的COPII囊泡在 免疫，代表了理解生物学和鉴定SEC23作为一个新的新的方向 减轻allo-HCT后T细胞同种异体反应的治疗目标。它的基础是小说的初稿 数据，将应用最先进的方法，利用协同和互补的小鼠和人体模型系统， 并得到具有必要专业知识的合作调查员的支持。如果成功，将提供基本的机制 对T细胞同种异体免疫的洞察与异体血细胞移植和实体器官移植排斥反应的直接关系 也可能对自身免疫、感染免疫有广泛的影响。