COPII dependent regulation of T cell alloimmunity

T 细胞同种免疫的 COPII 依赖性调节

基本信息

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
项目类别：
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

项目摘要

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 细胞在适应性免疫反应中发挥着核心作用，它们有助于保护性免疫反应和致病性免疫反应。过程，例如分别发生移植物抗白血病（GVL）和移植物抗宿主病（GVHD）同种异体造血细胞（allo-HCT）支持T细胞同种免疫的分子机制。对同种异体反应性 T 细胞中新分子靶标的识别可能会带来更好的结果。利用异基因 HCT，这是一种针对许多血液学和遗传性疾病的有效疗法。被同种异体抗原激活后，会发生代谢重编程，上调转录和翻译。 mRNA 翻译后，许多细胞蛋白从内质网 (ER) 流出到高尔基体（ER 至高尔基体途径）在运输至高尔基体之前进行适当的翻译后修饰最终的细胞内定位或细胞外分泌到高尔基体的运输是由保守的外套介导的。蛋白质复合物 II (COPII) 囊泡由蛋白质异二聚体组成，在其中至关重要。这些是 SEC23 蛋白7。SEC23 依赖性 COPII 介导的 ER 在 T 细胞中的高尔基体转运。作为初步数据，该提案将解决上述知识空白。产生的几种新型 SEC23 转基因小鼠，已获得 IRB 批准获得罕见的 Sec23b 突变遗传病患者和健康人类样本用于补充小鼠和人类研究，以测试中心假设是 Sec23 突变破坏 COPII 将降低体外 T 细胞同种免疫体内的具体目标（SA）是： SA 1：确定 SEC23B 依赖性 COPII 通路破坏对传统供体 T 的影响细胞 (Tcons) 对实验性同种异体 HCT 后结果的影响 SA 2：确定 SEC23 依赖性 COPII 囊泡调节的分子和遗传机制 T 细胞功能。因此，我们的建议探索了一条迄今为止未经研究的途径，即 SEC23 依赖性 COPII 囊泡在免疫并代表了理解生物学和将 SEC23 鉴定为新型药物的新方向减轻 allo-HCT 后 T 细胞同种异体反应的治疗目标是基于初步新颖的。数据，将应用最先进的方法，利用协同和互补的小鼠和人类模型系统，并得到具有必要专业知识的联合研究人员的支持，如果成功，将提供基本机制。对 T 细胞同种免疫的见解对同种异体 HCT 和实体器官同种移植排斥有直接影响，以及也可能对自身免疫、传染性免疫产生广泛的影响。