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: 10226915
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 192.44万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226915
• 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; Maintenance; Malignant Neoplasms; Modality; Modeling; Molecular; Monitor; Mus; Natural regeneration; Output; Peripheral; Phenotype; Pre-Clinical Model; Production; Quality of life; Reagent; Regenerative capacity; 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; immune function; immune system function; immunosenescence; improved; life history; lymph nodes; mouse model; neoplastic cell; novel; peripheral lymphoid organ; programs; response; secondary lymphoid organ

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会影响数百万老年人，减少 全球生活的长度和质量，对社会造成了巨大的经济燃烧。但是，需求 数十年的研究，恢复老年人的保护性免疫仍然难以捉摸。一个关键因素 导致与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。那， T细胞功能的恢复活力是非常需要的，以增强保护性免疫和整体 老年人的健康范围。 该T细胞复兴程序项目集中在两个关键问题上：（1）为什么TN单元格数和 功能随着年龄的增长而检测到； （2）怎么做？该程序的前提是TN单元 衰老是多因素的，只能通过靶向多个缺陷来解决。胸腺互动和 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 TN细胞维持和功能在周围的功能下降而复杂化。这些缺陷加在一起 侵蚀较旧的免疫系统检测和消除传染性剂和肿瘤细胞的能力，以及 适当地防止自身免疫。我们的目标是确定减少胸腺的机理原因 功能以及T细胞在次级淋巴机构中的维持和活性受损（例如淋巴） 节点，衰老。然后，我们将制定合并的策略以改善这些缺陷以改善 在古老的情况下进行免疫防御。我们的假设是对两个胸腺的机械解剖 需要生产和周围TN细胞维护才能制定和测试有效干预措施 对于较早的免疫系统修订。 该领域的专家领导的四个集成项目，由四个尖端核心的支持，将测试这一点 假设并实现以下程序目标：1。定义胸腺和次要的机械变化 淋巴器官老化； 2。通过比较胸腺的进展来产生人鼠的时间表 小鼠和人类的淋巴结和T细胞衰老； 3。确定内源性再生能力 在整个生命周期内胸腺和继发性淋巴管基质； 4。设计和测试修订策略 改善胸腺波西斯和周围T细胞的维持和功能，从而增强保护性免疫组织化学。 在这个支持时期，上述目标将提供大量的基础知识，这些知识将被转化为 临床前模型，并在人类鼠标时间表的帮助下被中毒，以转化为老年人。