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: 9755287
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 198.99万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755287
• 关键词: Address; Affect; Age; Aging; Archives; Autoimmune Diseases; Autoimmunity; Bioinformatics; Biometry; Cell Aging; Cell Count; Cell Maintenance; Cell Survival; Cell physiology; Cells; Communicable Diseases; Communication; Competence; Defect; Dissection; Economic Burden; Elderly; Event; Failure; Gene Expression Profiling; Genetic; Genetic Models; Goals; Healthcare; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Impairment; Individual; Infection; Infectious Agent; Informatics; Injury; Intervention; Knowledge; Laboratories; Length; Life; Life Stress; Longevity; Lymphoid; Maintenance; Malignant Neoplasms; Modality; Modeling; Molecular; Monitor; Mus; Natural regeneration; Organ; Output; Peripheral; Phenotype; Pre-Clinical Model; Production; Quality of life; Reagent; Rejuvenation; Research; Role; Sampling; Savings; Self Tolerance; Signal Transduction; Societies; Spleen; Standardization; Statistical Data Interpretation; Stress; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; TimeLine; Translating; Translations; age related; aged; animal tissue; comparative; data sharing; design; effective intervention; experience; health economics; healthspan; high throughput analysis; human model; immune function; immune system function; immunosenescence; improved; life history; lymph nodes; mouse model; neoplastic cell; novel; programs; regenerative; response

Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults, reducing length and quality of life across the globe and inflicting a massive economic burden on society. 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. Thus, rejuvenation of T cell function is highly desirable in order to enhance protective immunity and overall healthspan in older adults. 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 an early event leading to immunosenescence. This reduction is compounded by a decline 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. Our goal is to identify mechanistic reasons behind reduced thymic function as well as impaired maintenance and activity of T cells in secondary lymphoid organs, such as lymph nodes, with aging. We will then develop combined strategies to ameliorate these defects in order to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects to both thymic production AND peripheral TN cell maintenance is required to formulate and test effective interventions for immune system rejuvenation in the elderly. Four 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 thymic and secondary lymphoid organ aging; 2. Generate the Human-Mouse Timeline by comparing the progression of thymus, lymph node and T cell aging in mice and humans; 3. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 4. Devise and test rejuvenation strategies to improve thymopoiesis 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, with the help of the Human-Mouse Timeline, be poised for translation to older adults.

传染病、癌症和自身免疫性疾病影响着数亿老年人， 这给地球仪的寿命和生活质量带来了巨大的影响，并给社会带来了巨大的经济负担。但尽管 经过几十年的研究，恢复老年人的保护性免疫力仍然是一个难题。一个关键因素 导致年龄相关的免疫下降的原因是幼稚T（TN）细胞数量和功能的丧失。因此，本发明的目的是， 为了增强保护性免疫和整体免疫， 老年人的健康状况。 这个T细胞再生计划项目集中在两个关键问题上：（1）为什么TN细胞数量和 功能随年龄增长而退化;（2）对此可以做些什么？该方案的前提是TN细胞 老化是多因素的，只能通过针对多个缺陷来解决。胸腺退化和 导致T细胞产生的下降是导致免疫衰老的早期事件。这种减少是 伴随着TN细胞维持和外周功能的下降。这些缺陷联合收割机结合起来， 削弱老年免疫系统检测和消除感染因子和肿瘤细胞的能力， 来预防自身免疫我们的目标是确定胸腺减少背后的机械原因， 功能以及受损的维持和次级淋巴器官，如淋巴 节点，随着年龄的增长。然后，我们将制定组合策略来改善这些缺陷，以提高 老年人的免疫防御我们的假设是，对胸腺缺陷的机械解剖 需要对生产和外围TN单元进行维护，以制定和测试有效的干预措施 用于老年人的免疫系统恢复。 由该领域专家领导的四个综合项目，由四个尖端核心支持，将对此进行测试 假设并实现以下计划目标：1。定义胸腺和继发性 淋巴器官老化; 2.通过比较胸腺的进展生成人-小鼠时间轴， 小鼠和人的淋巴结和T细胞老化; 3.确定内源性再生能力 胸腺和次级淋巴器官基质在整个生命周期; 4.设计和测试恢复策略， 改善胸腺和外周T细胞维持和功能，从而增强保护性免疫。 在此支持期间，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，并在人-小鼠时间轴的帮助下，准备翻译到老年人。