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

预防、延缓或逆转与衰老相关的胸腺退化是一个广受欢迎的治疗目标 具有显著改善老年人免疫功能和健康寿命的潜力。胸腺退化 在儿童时期开始，并在此后进行，继续产生T细胞，这些T细胞在不断恶化的 微环境和提高的可能性，内卷的过程本身可能会产生亚功能T 细胞比较老年小鼠和年轻小鼠的退化研究仅研究退化的终末期。的 胸腺对多种应激也高度敏感。在一个受控的环境中， 环境和人类生活在世界上可以显着影响胸腺的速度和程度， 内卷化和反弹的能力。有越来越多的证据表明，在表达的变化， FOXN 1转录因子可能直接调控初始退化。我们的初步数据显示， 应激反应基因被FOXN 1抑制，随着衰老在胸腺上皮细胞（TEC）中上调， 可能介导胸腺退化的一些关键方面。这些数据直接暗示压力是一种潜在的 退化的重要方面，在动物模型中研究不足，但可能影响调节 人类的退化 该项目的前提是，开发小鼠胸腺退化模型， 免疫衰老包括更准确地模拟人类状况的参数， 为人类设计治疗策略提供相关数据。基于这一前提，我们建议使用新的 计算方法，以产生人类和小鼠胸腺退化的数据驱动比较， 测试具有加速退化的小鼠品系是否更好地模拟胸腺退化对 人外周血T细胞，并研究应激对年龄相关性退化的影响。我们还将 检验TEC对重复压力的反应会损害反弹能力的假设， Atf 3应激反应基因随着衰老而上调，并促进胸腺的关键方面。 对合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退化及其对外周T细胞影响的新模型 随着年龄的变化。与项目3和4以及核心A-C一起，人类-小鼠比较将 生成人鼠时间轴，这不仅是程序的关键资源， 社区的参考。该项目的这一方面和其他方面将与其他项目成果协同作用 并告知核心D中干预测试的设计和解释。

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.