Back to Basics: T Cellular Control of Nod2 in Uveitis

回到基础：T 细胞对葡萄膜炎中 Nod2 的控制

• 批准号: 10615007
• 负责人: HOLLY Lallman ROSENZWEIG
• 金额: $ 31.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615007
• 关键词: 3-Dimensional; Address; Affect; Animals; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Autoimmunity; Back; Blau syndrome; CD4 Positive T Lymphocytes; Calibration; Cell physiology; Cells; Chronic; Classification; Clinical Data; Complex; Data; Development; Disease; Disease model; Economic Burden; Environment; Evaluation; Event; Evolution; Eye; Eye diseases; Family; Future; Generations; Genetic Determinism; Goals; Granulomatous; Health; Homeostasis; IL17 gene; Immune; Immunologic Receptors; Immunomodulators; Impairment; Individual; Inflammation; Inflammatory; Interleukin-2; Investigation; Life; Link; Mediating; Medical; Methodology; Modeling; Molecular; Morbidity - disease rate; Mutation; Myelogenous; Natural Immunity; Pain; Pathogenesis; Pathogenicity; Patients; Population; Prevention; Process; Production; Proteins; Receptor Activation; Receptor Signaling; Regulation; Repression; Research; Role; Shapes; Signal Transduction; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Intervention; Thymocyte Development; Thymus Gland; Tissues; Toll-like receptors; Uveitis; Vision; Visual; Visual impairment; Work; arthropathies; autocrine; autoimmune uveitis; autoreactive T cell; autoreactivity; body sense; central tolerance; clinically relevant; cytokine; design; direct application; experimental study; insight; interstitial retinol-binding protein; microbial; novel; novel therapeutic intervention; operation; pathogen; pathogenic microbe; preservation; receptor; response; sensor; skin disorder; social; targeted treatment; thymocyte; treatment strategy

PROJECT SUMMARY: Uveitis is a complex set of diseases that together constitute ~15% of visual morbidity worldwide. For many patients, uveitis can be a chronic life-long disease for which therapies may manage painful inflammation, but do not provide a cure. For some with rheumatologic conditions, uveitis is also accompanied by diseases of the joint, skin, or gut. Thus there is an urgent, unmet need to define key mechanisms of uveitis because of its significant associated personal, social, and economic burdens. Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated to avoid excessive inflammation and tissue destruction. Such regulation is especially important in the eye, where multiple factors and processes act together to limit inflammation so as to preserve the delicate cells and tissues critical to vision. The body senses potentially pathogenic microbes in the environment via innate immune receptors, which are classified into distinct families such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs). One NLR, Nod2, not only serves as an intracellular sensor of microbial and foreign motifs, but is causally linked to non-infectious granulomatous uveitis in Blau syndrome. Using a model of T cell-mediated uveitis, experimental autoimmune uveitis (EAU), an unexpected novel role was identified for Nod2 in protection against autoimmune uveitis. Such protection was found to be conferred by CD4+ T cells and involved Nod2 modulation of the pathogenic capacity of a subset of CD4+ T cells, Th17 cells, by controlling their production of the cytokine IL-17. Based on these findings, as well as additional key preliminary data, this proposal aims to systematically probe the spectrum of actions by which Nod2 could impact the evolution of disease-causing T cells responses. Using methodologies that encompass molecular, cellular, and whole animal evaluation, experiments will test the central hypothesis that Nod2 is a critical immunomodulator of autoreactive T cells that cause uveitis, and are organized in three Specific Aims: 1) Delve into how Nod2 alters the uveitogenic potential of individual or populations of CD4+ T cells; 2) Elucidate the effects of Nod2 on the internal operations of T cells that intersect with T-cell receptor (TCR) signaling and T cell function; and 3) Determine whether Nod2 influences T cell development and maturation of uveitogenic T cells. The role of Nod2 in autoimmune diseases is an area that has yet to be more fully clarified. This research could potentially open up new avenues of investigation that could ultimately result in novel strategies for therapeutic intervention of uveitis, as well as of other vision-threatening diseases.

项目概要： 葡萄膜炎是一组复杂的疾病，在全球范围内共同构成约15%的视觉发病率。对于许多 葡萄膜炎可能是一种慢性终身疾病，治疗方法可以控制疼痛的炎症，但 无法治愈对于一些风湿性疾病，葡萄膜炎也伴随着疾病的 关节皮肤或内脏因此，由于葡萄膜炎的发病机制， 严重的个人、社会和经济负担。先天免疫作为第一道防线 对抗微生物病原体，是一种必须严格调节以避免过度炎症的反应， 组织破坏这种调节在眼睛中尤其重要，因为在眼睛中有多种因素和过程起作用 一起来限制炎症，以保护对视力至关重要的脆弱细胞和组织。身体感觉到 潜在的致病微生物在环境中通过先天免疫受体，这是分类为 不同的家族，如Toll样受体（TLR）或NOD样受体（NLR）。一个NLR，Nod 2，不仅 作为微生物和外源基序的细胞内传感器，但与非感染性 Blau综合征的肉芽肿性葡萄膜炎使用T细胞介导的葡萄膜炎模型， 在自身免疫性葡萄膜炎（EAU）中，鉴定了Nod 2在保护免受自身免疫性葡萄膜炎中的意想不到的新作用。等 发现保护作用由CD 4 + T细胞赋予，并涉及Nod 2对致病能力的调节 的CD 4 + T细胞，Th 17细胞的子集，通过控制它们的细胞因子IL-17的生产。基于这些 调查结果，以及其他关键的初步数据，这项建议的目的是系统地探讨频谱 Nod 2可能影响致病性T细胞反应的演变。使用方法 包括分子、细胞和整个动物评估，实验将检验中心假设 Nod 2是导致葡萄膜炎的自身反应性T细胞的关键免疫调节剂，并组织成三个 具体目的：1）深入研究Nod 2如何改变CD 4 + T细胞个体或群体的葡萄膜形成潜力 2）阐明Nod 2对与T细胞受体交叉的T细胞内部运作的影响 (TCR)3）确定Nod 2是否影响T细胞发育， 葡萄膜原性T细胞的成熟。Nod 2在自身免疫性疾病中的作用是一个有待进一步研究的领域。 完全澄清。这项研究可能会开辟新的调查途径，最终可能导致 在葡萄膜炎以及其他威胁视力的疾病的治疗干预的新策略中。

项目成果

Epigenetic Regulation of Optic Nerve Development, Protection, and Repair.

• DOI: 10.3390/ijms23168927
• 发表时间: 2022-08-10
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Ashok, Ajay;Pooranawattanakul, Sarita;Tai, Wai Lydia;Cho, Kin-Sang;Utheim, Tor P.;Cestari, Dean M.;Chen, Dong Feng
• 通讯作者: Chen, Dong Feng