COPII dependent regulation of T cell alloimmunity

T 细胞同种免疫的 COPII 依赖性调节

• 批准号: 10161857
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161857
• 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