COPII dependent regulation of T cell alloimmunity

T 细胞同种免疫的 COPII 依赖性调节

• 批准号: 10744487
• 负责人: PAVAN REDDY
• 金额: $ 62.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-19 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744487
• 关键词: Alloantigen; Allogenic; Autoimmunity; Biological Models; Biology; Capsid Proteins; Cell physiology; Cell secretion; Cells; Cellular Metabolic Process; Compensation; Complex; Data; Defect; Development; Dysplasia; Endoplasmic Reticulum; Future; Genetic; Genetic Diseases; Genetic Transcription; Golgi Apparatus; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hereditary Disease; Human; Immune; Immunity; In Vitro; Institutional Review Boards; Knowledge; Lipids; Location; Mammals; Mediating; Metabolic; Metabolism; Methods; Molecular; 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 Activation; 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; mRNA Translation; 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细胞在适应性免疫反应中起着核心作用。它们既能起到保护作用， 过程，如移植物抗白血病（GVL）和移植物抗宿主病（GVHD），分别在 异基因造血细胞（allo-HCT）。T细胞同种免疫的分子机制 并没有被充分理解。在同种异体反应性T细胞中鉴定新的分子靶点可以更好地 利用allo-HCT，一种针对许多血液学和遗传性疾病的有效疗法。初始T细胞 在被同种异体抗原激活后，经历代谢重编程，上调转录和翻译。 从mRNA翻译后，许多细胞蛋白质从内质网（ER）排出， 高尔基体（ER至高尔基体途径）进行适当的翻译后修饰，然后转运至 最终细胞内定位或细胞外分泌。ER向高尔基体的转运是由保守的Coat 蛋白复合物II（COPII）囊泡。COPII囊泡由蛋白质的异源二聚体组成，这在 它们是SEC 23蛋白7。依赖sec 23的COPII介导的T细胞内质网向高尔基体转运的作用 免疫力未知。这项建议将弥补上述知识差距。作为初步数据， 产生了几种类型的新的SEC 23转基因小鼠，具有IRB批准的获得罕见的SEC 23 b突变 用于补充鼠和人研究的遗传疾病患者和健康人样品，以测试 中心假设，Sec 23突变对COPII的破坏将降低体外T细胞同种免疫力， in vivo.具体目标（SA）是： SA 1：为了确定在常规供体T细胞中SEC 23 B依赖性COPII途径的破坏的影响， 细胞（Tcons）对实验性同种异体HCT后结局的影响 SA 2：确定SEC 23依赖性COPII囊泡在调节细胞凋亡中的分子和遗传机制。 T细胞的功能。 因此，我们的建议探索了迄今为止未研究的途径，SEC 23依赖性COPII囊泡在 它代表了理解生物学的一个新方向，并将SEC 23鉴定为一种新的免疫抑制剂。 治疗靶点以减轻allo-HCT后的T细胞同种异体反应性应答。它是基于小说初步 数据，将应用现有技术的方法，利用协同和互补的鼠和人模型系统， 并得到具有必要专门知识的共同调查员的支持。如果成功，将提供基本的机械 深入了解T细胞同种免疫与allo-HCT和实体器官移植排斥反应的直接关系， 也可能对自身免疫和感染性免疫有广泛的影响。