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.

抽象的 T细胞在适应性免疫调查中起着核心作用。它们有助于保护和致病性 过程，例如移植物与白血病（GVL）和移植物与宿主疾病（GVHD），之后 同种异体造血细胞（Allo-HCT）。 T细胞同种免疫力支撑的分子机制 不是很好理解。同种反应性T细胞中新型分子靶标的鉴定可能导致更好 利用Allo-HCT，这是一种潜在的疗法，以抵抗许多血液学和遗传疾病。幼稚的T细胞 同种抗原激活后，经过代谢重编程，上调转录和翻译。 从mRNA翻译后，许多细胞蛋白从内质网（ER）出口到 高尔基体（ER到高尔基途径）进行适当的翻译后修饰，然后再运输到 最终的细胞内位置或细胞外分泌。 ER到高尔基运输是由配置的外套介导的 蛋白质复合物II（COPII）蔬菜。 Copii蔬菜由蛋白质的异二聚体制成，至关重要 是Sec23蛋白7。 Sec23依赖的COPII介导的ER的作用是T细胞中高尔基体转运的作用 免疫是未知的。该提案将解决上述知识差距。作为初步数据，我们有 生成了几种类型的新型SEC23转基因小鼠，具有IRB批准的稀有SEC23B突变的访问 遗传疾病患者和健康的人类样本用于完整的鼠和人类研究，以测试 中心假设，即Sec23突变对COPII的破坏将在体外降低T细胞同种异体免疫性 体内。具体目的（SA）是： SA 1：确定SEC23B依赖性COPII途径中断在常规供体中的影响 实验性同种异体HCT后的结局细胞（TCON） SA 2：确定Sec23依赖Copii蔬菜的分子和遗传机制 T细胞功能。 因此，我们的建议探讨了迄今未研究的途径，Sec23依赖Copii蔬菜的作用 免疫力，代表理解生物学的新方向，并将Sec23识别为新颖 治疗靶标可减轻Allo-HCT后T细胞同种反应反应。它基于新颖的初步 数据将采用最新方法，利用协同和完整的鼠类和人类模型系统， 并得到与必要的专家共同投资者的支持。如果成功，将提供基本的机械 对T细胞Allo免疫的见解，对Allo-HCT和固体器官Allo-Graft排斥反应有直接影响，以及 可能对自身免疫性，传染性免疫学有广泛的影响。