Tissue-Specific Mechanisms of Regulatory T Cells in the CNS during Autoimmune Encephalomyelitis

自身免疫性脑脊髓炎期间中枢神经系统调节性 T 细胞的组织特异性机制

• 批准号: 10420232
• 负责人: Shivashankar Othy
• 金额: $ 49.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420232
• 关键词: Ablation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmune; Autoimmune Diseases; Autoimmunity; Axon; Behavior; CNS autoimmunity; Calcium; Candidate Disease Gene; Cell Survival; Cell Therapy; Cell membrane; Cell physiology; Cells; Clinical Trials; Clonal Expansion; Clone Cells; Communicable Diseases; Complex; Crowding; Cues; Detection; Development; Ensure; Environment; Evaluation; Experimental Autoimmune Encephalomyelitis; Failure; Functional disorder; Genetic; Goals; Healthcare; Home; Homeostasis; Image; Immune; Immune System Diseases; Immune system; Immunosuppression; Infection; Inflammation; Interleukin-2; Ion Channel; Knowledge; Label; Longitudinal Studies; Malignant Neoplasms; Mediating; Molecular; Monitor; Movement; Multiple Sclerosis; Myelin; Neuraxis; Organ; Organ Transplantation; Outcome; Pathologic; Pathway interactions; Pattern; Permeability; Phase; Physiological; Piezo 1 ion channel; Play; Positioning Attribute; Process; Proteins; Recovery; Regulatory T-Lymphocyte; Reporter; Resolution; Role; Scanning; Signal Transduction; Spinal Cord; Surface; T-Cell Receptor; Testing; Therapeutic; Tissues; Transgenic Mice; Visualization; autoinflammatory; axon injury; base; cell behavior; cell motility; cost; experimental study; fighting; follow-up; forkhead protein; immune imaging; immunological synapse; immunoregulation; in vivo; insight; lymphoid organ; mouse model; neuroinflammation; preservation; ratiometric; remyelination; repaired; response; targeted treatment; therapeutic evaluation; therapeutic target; tissue repair; two photon microscopy; two-photon

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) and other autoimmune diseases constitute a major healthcare burden at a cost of >$125 billion per year. Autoimmune disorders arise from a failure of immunoregulatory networks. Regulatory T (Treg) cells expressing transcription factor forkhead box protein 3 (Foxp3) are indispensable components of these networks. Moreover, recent studies from several groups suggest that Treg cells also facilitate tissue repair, in addition to exerting immunosuppression. During autoimmune diseases, Treg cells are activated in lymphoid organs and home to non-lymphoid target tissues where they persist in specialized niches to limit inflammation and facilitate tissue repair. Our overall goal is to determine how these Treg cell niches operate in the central nervous system (CNS) to ameliorate autoimmune neuroinflammation at cellular and molecular levels. Direct visualization of cell behavior often leads to surprises, new hypotheses, and follow-up experiments contributing to a better understanding of the mammalian immune system, and how autoimmunity and infectious diseases can be effectively treated. Building on our expertise in two-photon (2-P) imaging at the cellular level, and Ca2+ signaling at the molecular level, we will use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to: 1) elucidate the local cues that drive survival, functional organization in niches, and motility behaviors of Treg cells in the spinal cord; 2) investigate how Treg cells selectively target processes that incite neuroinflammation. Our experimental approach includes evaluation of the Piezo1 channels as promising therapeutic targets to selectively expand Treg cells, an ideal strategy to curb ongoing autoinflammatory responses while preserving the immune system’s ability to fight new infections. Although this proposal is targeted specifically to MS, in a broader context our project will provide fundamental insights into how Treg cells fine-tune tissue inflammation so that better Treg-modifying therapies can be developed for autoimmune disorders, organ transplantation, cancer, and infectious diseases.

项目摘要/摘要 多发性硬化症（MS）和其他自身免疫性疾病构成了主要的医疗保健伯恩，费用> 125美元 每年十亿。自身免疫性疾病源于免疫调节网络的失败。调节t（Treg） 表达转录因子叉盒蛋白3（FOXP3）的细胞是必不可少的组成部分 网络。此外，来自几个小组的最新研究表明，Treg细胞也促进了组织修复 除了施加免疫抑制。在自身免疫性疾病期间，Treg细胞在淋巴样中被激活 器官和非淋巴目标时间的住所，在这些目标时间内，他们坚持使用专门的壁nir以限制注射 并促进组织修复。我们的总体目标是确定这些Treg细胞生态位如何在中央运作 神经系统（CNS）在细胞和分子水平上改善自身免疫性神经炎症。直接的 细胞行为的可视化通常会导致惊喜，新假设和后续实验，从而导致 更好地了解哺乳动物免疫系统，以及自身免疫性和传染病如何 有效治疗。基于我们在细胞水平的两光子（2-P）成像的专业知识和Ca2+ 在分子水平的信号传导，我们将使用实验性自身免疫性脑脊髓炎（EAE）小鼠模型 MS至：1）阐明驱动生存，壁ni和运动行为的局部线索 脊髓中的Treg细胞； 2）研究Treg细胞如何选择性地靶向吸引的过程 神经炎症。我们的实验方法包括对压电1通道的评估 选择性扩展Treg细胞的治疗靶标，这是抑制正在进行的自身炎症的理想策略 在保留免疫系统对抗新感染的能力的同时，会做出反应。尽管该提议针对 特别针对MS，在更广泛的背景下，我们的项目将提供有关Treg细胞如何微调的基本见解 组织注射，以便可以为自身免疫性疾病开发更好的Treg修改疗法 移植，癌症和传染病。