Project 2: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

项目2：老年胸腺对损伤和恢复活力的反应 摘要 即使胸腺对急性损伤非常敏感，如感染、休克或 常见的癌症治疗方法，如细胞减少性化疗或放射治疗，它也具有非凡的能力 用于内源性修复。然而，这种能力随着年龄的增长而下降，是老年人的主要临床障碍。 接受免疫侮辱的患者，如常见的癌症细胞减少疗法和 造血干细胞移植(HSCT)所需的调节。 这个项目的前提是胸腺对急性损伤的再生反应被削弱 年龄并与年龄相关的胸腺退缩相关。我们将比较和对比我们所知道的 支持幼年动物胸腺再生的细胞和分子途径 在正常胸腺老化过程中小鼠的反应；并开发合理的干预策略以改善 衰老小鼠的再生。在这个项目中，我们将全面评估内生再生 寿命响应(SA1)，进行研究以更好地了解 内源性胸腺再生及其在老年小鼠中的破坏(SA2)，以及已知和推定的测试 确定它们在促进老年组织中胸腺生成的有效性的策略 损坏(SA3)。 我们的项目与本P01的其他项目和核心有多个互动点，包括提供 探讨内皮细胞(ECs)和BMP4在胸腺和SLO衰老中的作用。加在一起，这些 旨在支持P01的首要目标，即确定导致胸腺缺陷的机制 幼稚T细胞的产生随年龄增长。概述的机制和临床前研究有可能 确定胸腺再生的重要新途径，这可能导致临床方法 增强因年龄相关性退缩而导致胸腺严重受损的患者的T细胞免疫功能。

PROJECT 2: RESPONSE OF THE AGED THYMUS TO INJURY AND REJUVENATION ABSTRACT Even though the thymus is is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. However, this capacity declines with age and is a major clinical hurdle in elderly patients who receive an immune insult such as that caused by common cancer cytoreductive therapies and the conditioning required for hematopoietic stem cell transplantation (HSCT). The premise of this project is that the thymic regenerative response to acute injury is weakened with age and correlates with age-related thymic involution. We will compare and contrast what we know about the cellular and molecular pathways that underpin thymic regeneration in young animals, to the regenerative response in mice during normal thymic aging; and develop rational intervention strategies to improve regeneration in aged mice. In this project, we will comprehensively assess the endogenous regenerative response over lifespan (SA1), perform studies to better understand the underlying mechanisms governing endogenous thymic regeneration and their breakdown in aged mice (SA2), and test known and putative strategies to determine their effectiveness in promoting thymopoiesis in aged tissue that has undergone damage (SA3). Our project has multiple points of interaction with the other projects and cores of this P01, including providing the basis for exploring the role of endothelial cells (ECs) and BMP4 in thymic and SLO aging. Together, these aims support the overarching goal of the P01 to identify the mechanisms responsible for defects in thymic production of naïve T cells with age. The mechanistic and pre-clinical studies outlined have the potential to define important novel pathways underlying thymic regeneration, which could result in clinical approaches to enhance T cell immunity in patients whose thymus has been decimated due to age-related involution.