Project 1: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

项目 1：T 细胞衰老和再生的胸腺和外周方面

• 批准号: 10226921
• 负责人: Nancy R Manley
• 金额: $ 24.49万
• 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/10226921
• 关键词: Address; Affect; Age; Aging; Animal Model; Cell Aging; Cell Differentiation process; Cell physiology; Characteristics; Childhood; Collaborations; Communities; Computing Methodologies; Controlled Environment; Data; Event; Experimental Designs; Genes; Genetic; Goals; Human; Immune; Immunocompetence; Intervention; Longevity; Maintenance; Mediating; Modeling; Molecular; Mouse Strains; Mus; Outcome; Pathway interactions; Peripheral; Phenotype; Process; Puberty; Reference Values; Rejuvenation; Resources; Rodent; Role; Sampling; Signal Transduction; Stress; Study models; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; TimeLine; Up-Regulation; Weaning; Wild Type Mouse; activating transcription factor 3; age related; base; biological adaptation to stress; design; experimental study; healthspan; human model; human old age (65+); immune function; immune health; immunosenescence; improved; insight; life history; loss of function; mouse model; mutant; novel; prevent; programs; response; transcription factor

Preventing, delaying, or reversing aging-related thymic involution is a widely sought-after therapeutic goal with the potential to significantly improve immune function and health-span in aging humans. Thymic involution initiates in childhood, and is progressive thereafter, continuing to produce T cells that develop in a deteriorating microenvironment and raising the possibility that the process of involution itself may produce sub-functional T cells. Studies of involution that compare old with young mice investigate only the end stage of involution. The thymus is also highly sensitive to many kinds of stress. The very different life histories of mice in a controlled environment and humans living in the world could significantly influence the rate and degree of thymus involution, and the capacity for rebound. There is accumulating evidence that changes in the expression of the FOXN1 transcription factor may directly regulate initial involution. Our preliminary data show that the Atf3 stress response gene is suppressed by FOXN1, up-regulated in thymic epithelial cells (TEC) with aging, and may mediate some key aspects of thymic involution. These data directly implicate stress as a potentially important aspect of involution that is understudied in animal models, but may impact efforts to modulate involution in humans. This project is based on the premise that developing mouse models of thymic involution and immunosenesensce to include parameters that more accurately mimic the human condition will generate more relevant data for devising therapeutic strategies in humans. Based on this premise we propose to use novel computational approaches to generate a data-driven comparison of human and mouse thymic involution, to test whether a mouse strain with accelerated involution better mimics the effects of thymic involution on peripheral T cells in humans, and to investigate the effects of stress on age-associated involution. We will also test the hypothesis that the TEC response to repeated stress compromises the capacity for rebound with aging, and that the Atf3 stress response gene is up regulated with aging and promotes key aspects of thymus involution. These experiments will directly address the differences between mouse and human lifespan and life history, to develop and test new models for investigating thymic involution and its effects on peripheral T cell changes with aging. Together with Projects 3 and 4 and Cores A-C, the human-mouse comparisons will generate the Human-Mouse Timeline that will be not only a key resource to the Program, but a valuable reference for the community. This and other aspects of this Project will synergize with other Project outcomes and inform the design and interpretation of interventions testing in Core D.

预防、延迟或逆转与衰老相关的胸腺退化是一个广泛追捧的治疗目标 有可能显着改善老年人的免疫功能和健康寿命。胸腺复旧 始于儿童期，此后逐渐发展，继续产生在恶化的环境中发育的 T 细胞 微环境并提高了内卷过程本身可能产生亚功能T的可能性 细胞。比较老年小鼠和年轻小鼠的复旧研究仅调查复旧的末期。这 胸腺对多种压力也高度敏感。受控小鼠的生活史截然不同 环境和生活在世界上的人类可以显着影响胸腺的速率和程度 卷缩能力和反弹能力。越来越多的证据表明，表达的变化 FOXN1转录因子可能直接调节初始复旧。我们的初步数据显示 Atf3 应激反应基因受到 FOXN1 抑制，在胸腺上皮细胞 (TEC) 中随着衰老而上调，并且 可能介导胸腺复旧的一些关键方面。这些数据直接表明压力是潜在的 内卷的一个重要方面，在动物模型中尚未得到充分研究，但可能会影响调节的努力 人类的内卷化。 该项目的前提是开发小鼠胸腺退化模型和 免疫感应包括更准确地模拟人类状况的参数将产生更多 用于制定人类治疗策略的相关数据。基于这个前提我们建议使用新颖的 计算方法来生成人类和小鼠胸腺退化的数据驱动比较，以 测试加速复旧的小鼠品系是否能更好地模拟胸腺复旧的影响 人类外周 T 细胞，并研究压力对与年龄相关的退化的影响。我们也会 检验以下假设：TEC 对重复应力的响应会损害反弹能力 Atf3 应激反应基因随着衰老而上调，并促进胸腺的关键方面 内卷化。这些实验将直接解决小鼠和人类寿命和寿命之间的差异 历史，开发和测试研究胸腺复旧及其对外周 T 细胞影响的新模型 随着年龄的增长而变化。与项目 3 和 4 以及核心 A-C 一起，人鼠比较将 生成人鼠时间线，这不仅是该计划的关键资源，而且是一个有价值的资源 供社会参考。该项目的这一方面和其他方面将与其他项目成果产生协同作用 并为核心 D 中干预测试的设计和解释提供信息。