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影响着数亿老年人，减少了 全球范围内生活的长度和质量，并给社会造成巨大的经济负担。然而，尽管 经过数十年的研究，恢复老年人的保护性免疫力仍然难以实现。一个关键因素 幼稚 T (TN) 细胞数量和功能的丧失是导致与年龄相关的免疫衰退的原因。因此， 为了增强保护性免疫力和整体能力，T 细胞功能的复兴是非常必要的。 老年人的健康寿命。 该 T 细胞复兴计划项目围绕两个关键问题：(1) 为什么 TN 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？该方案的前提是TN细胞 老化是多因素造成的，只能通过针对多种缺陷来解决。胸腺复旧和 由此导致的 T 细胞产量下降是导致免疫衰老的早期事件。这个减少量是 外周 TN 细胞维护和功能下降使情况更加复杂。这些缺陷综合起来 削弱旧免疫系统检测和消除感染因子和肿瘤细胞的能力，以及 正确防范自身免疫。我们的目标是确定胸腺减少背后的机制原因 次级淋巴器官（例如淋巴）中 T 细胞的功能以及维持和活性受损 节点，随着老化。然后我们将制定综合策略来改善这些缺陷，以改善 老年人的免疫防御。我们的假设是，胸腺和胸腺缺陷的机械解剖 需要维持生产和外周 TN 细胞以制定和测试有效的干预措施 用于老年人免疫系统的恢复。 由该领域专家领导、四位前沿核心支持的四个综合项目将对此进行测试 假设并实现以下计划目标： 1. 定义胸腺和次级的机制变化 淋巴器官老化； 2. 通过比较胸腺的进展来生成人-小鼠时间线， 小鼠和人类的淋巴结和 T 细胞老化； 3. 确定内源再生能力 整个生命周期中的胸腺和次级淋巴器官基质； 4. 制定并测试复兴策略 改善胸腺生成和外周T细胞的维持和功能，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，并在人鼠时间轴的帮助下，准备好转化为老年人。