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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要多发性硬化症 (MS) 和其他自身免疫性疾病构成主要医疗负担，费用超过 125 美元每年有 10 亿美元的自身免疫性疾病是由免疫调节网络 (Treg) 的故障引起的。表达转录因子叉头盒蛋白 3 (Foxp3) 的细胞是这些细胞不可缺少的组成部分。此外，几个小组最近的研究表明，Treg 细胞还促进组织修复。在自身免疫性疾病期间，Treg 细胞除了发挥免疫抑制作用外，还在淋巴中被激活。器官和非淋巴靶组织的所在地，它们持续存在于专门的生态位中以限制炎症我们的总体目标是确定这些 Treg 细胞生态位如何在中枢发挥作用。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。细胞行为的可视化常常会带来惊喜、新的假设和后续实验，从而有助于更好地了解哺乳动物的免疫系统，以及自身免疫和传染病如何影响凭借我们在细胞水平双光子 (2-P) 成像和 Ca2+ 方面的专业知识，得到有效治疗。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 的目的是：1）阐明驱动生存、生态位功能组织和运动行为的局部线索 2) 研究Treg细胞如何选择性地靶向激发的过程我们的实验方法包括评估 Piezo1 通道是否有希望。选择性扩增 Treg 细胞的治疗靶标，这是抑制持续性自身炎症的理想策略尽管这一提议是有针对性的，但同时保留了免疫系统抵抗新感染的能力。特别是对于 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炎症，以便开发更好的 Treg 修饰疗法来治疗自身免疫性疾病、器官移植、癌症和传染病。