Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

T 细胞衰老和再生的胸腺和外周方面

• 批准号: 10553988
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 271.3万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553988
• 关键词: 2019-nCoV; Address; Affect; Age; Aging; Archives; Autoimmune Diseases; Autoimmunity; Bone Marrow; COVID-19 pandemic; Cell Aging; Cell Count; Cell Maintenance; Cell Survival; Cell physiology; Cells; Communicable Diseases; Communication; Data Science; Defect; Deterioration; Dissection; Economic Burden; Economics; Elderly; Elements; Event; Failure; Gene Expression Profiling; Genetic Models; Goals; Health; Healthcare; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Impairment; Individual; Infection; Infectious Agent; Informatics; Injury; Intervention; Knowledge; Laboratories; Length; Life; Longevity; Maintenance; Malignant Neoplasms; Modality; Molecular; Monitor; Mus; Natural regeneration; Output; Pathway interactions; Peripheral; Phenotype; Pre-Clinical Model; Process; Production; Quality of life; Reagent; Regenerative capacity; Rejuvenation; Research; Role; Sampling; Savings; Science; Self Tolerance; Signal Transduction; Societies; Spleen; Standardization; Statistical Data Interpretation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Translating; Translations; Virus; age related; aged; animal tissue; central tolerance; comparative; data sharing; design; effective intervention; experience; healthspan; high throughput analysis; immune function; immune system function; immunosenescence; improved; lymph nodes; lymphoid organ; mortality; mouse model; neoplastic cell; novel; peripheral lymphoid organ; primary lymphoid organ; programs; response; secondary lymphoid organ; success; synergism; timeline

OVERALL- Abstract Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults. They reduce length and quality of life across the globe and inflict a massive economic burden on society, as vividly exemplified by the SARS-CoV-2 pandemic, that has claimed 93.1% of its victims amongst those 50 years and older, and 74.4% in those 64 and older. Yet, despite decades of research, restoring protective immunity in older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of naïve T (Tn) cell numbers and function, and their rejuvenation is highly desirable in order to enhance protective immunity and overall healthspan in older adults. The renewal of this T cell Rejuvenation Program Project is centered on two key questions: (1) why do Tn cell numbers and function deteriorate with age; and (2) what can be done about it? The premise of the program is that Tn cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and the resulting decline in T cell production is the earliest event leading to immunosenescence. This reduction is compounded by a decline in bone marrow function, as well as by defects in Tn cell maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against autoimmunity. In the first program period, we strongly confirmed our initial hypotheses that lymphoid organ stromal elements deteriorate earlier than previously thought, and in a manner to decisively erode immunity, with aging. We will build on the synergy and success of the initial program period, where discoveries in one project are critically informing science in others, and continue to identify mechanistic reasons behind reduced central and peripheral lymphoid organ function with aging. We will then develop combined strategies to ameliorate these defects to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects in both thymic production AND peripheral Tn cell maintenance is required to devise and test effective interventions for T cell rejuvenation in the elderly. Three integrated projects led by experts in the field, supported by four cutting-edge cores, will test this hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in primary and secondary lymphoid organ aging; 2. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 3. Relate the progression of murine thymus, lymph node (LN) and T cell aging phenotypes to humans; and 4. Devise and test rejuvenation strategies to improve thymopoiesis, T cell survival and peripheral T cell maintenance and function, so as to enhance protective immunity. Over this support period, the above goals will provide a wealth of basic knowledge that will be translated to preclinical models and be poised for translation to older adults.

总体-摘要 传染病、癌症和自身免疫性疾病影响着数亿老年人。他们 减少全球生活的长度和质量，给社会造成巨大的经济负担，正如 以 SARS-CoV-2 大流行为例，在过去 50 年中，93.1% 的受害者已死亡 年龄较大，64 岁及以上人群中这一比例为 74.4%。然而，尽管经过数十年的研究，恢复保护性免疫力 老年人仍然难以捉摸。导致与年龄相关的免疫下降的一个关键因素是丧失 幼稚 T (Tn) 细胞数量和功能及其恢复活力对于增强保护作用非常重要 老年人的免疫力和整体健康寿命。 此次T细胞复兴计划项目的更新围绕两个关键问题：（1）Tn为何 细胞数量和功能随着年龄的增长而退化； (2) 对此可以采取什么措施？方案的前提 Tn细胞衰老是多因素造成的，只能通过针对多种缺陷来解决。胸腺 退化和由此导致的 T 细胞产量下降是导致免疫衰老的最早事件。 骨髓功能下降以及 Tn 细胞缺陷加剧了这种减少 外围的维护和功能。这些缺陷结合起来削弱了老年人的免疫能力 系统检测和消除传染源和肿瘤细胞，并适当防范 自身免疫。在第一个项目期间，我们强烈证实了我们最初的假设，即淋巴器官 基质元素比之前想象的更早恶化，并以一种决定性削弱免疫力的方式， 随着衰老。我们将在初始计划期间的协同作用和成功的基础上再接再厉，其中的发现 项目正在为其他领域的科学提供批判性的信息，并继续确定减少背后的机械原因 中枢和外周淋巴器官的功能随衰老而变化。然后我们将制定综合策略 改善这些缺陷，提高老年人的免疫防御能力。我们的假设是机械 需要对胸腺生成和外周 Tn 细胞维护中的缺陷进行剖析，以设计和 测试老年人 T 细胞复兴的有效干预措施。 由该领域专家领导、四位尖端核心支持的三个综合项目将对此进行测试 假设并实现以下计划目标： 1. 定义初级和次级的机制变化 淋巴器官老化； 2.测定胸腺和次级淋巴的内源性再生能力 整个生命周期的器官基质； 3. 关联小鼠胸腺、淋巴结 (LN) 和 T 细胞衰老的进展 人类的表型； 4. 设计和测试恢复活力策略以改善胸腺生成、T 细胞存活 以及外周T细胞的维护和功能，从而增强保护性免疫力。 在此支持期内，上述目标将提供丰富的基础知识，这些知识将转化为 临床前模型并准备转化为老年人。