Response of aged thymus to injury and rejuvenation signals

项目1-摘要 尽管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疗法，它也有显著的 内源性修复能力。然而，这种能力随着年龄的增长而下降，是临床上的一个主要障碍。 接受免疫侮辱的老年患者，如常见的癌症细胞减少疗法引起的 以及造血干细胞移植(HCT)所需的条件。 这个项目的前提是胸腺对急性损伤的再生反应减弱。 与年龄相关，并与年龄相关的胸腺退化相关。我们将对我们所知道的进行比较和对比 关于支撑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再生反应；并制定合理的干预策略 促进衰老小鼠的再生。在这个项目中，我们将全面评估内生性 对寿命的再生反应，特别强调年龄的性别差异(SA1)； 更好地了解内源性胸腺再生的潜在机制及其机制的研究 老年小鼠的分解，关注炎症和促再生信号之间的平衡 急性损伤后死亡细胞(SA2)；并根据这些已知和 确定它们在促进老年组织胸腺生成方面的有效性的推定策略 已遭受损坏(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 关注造血和非造血基质微环境，Notch-DLL4的调控 交互，最重要的是，一个全面的共享测序数据集，可以利用 在整个项目中。这些目标和相互作用共同支持了P01的总体目标，即确定 胸腺幼稚T细胞产生缺陷随年龄增长的机制及发展方法 改进或逆转它们。因此，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 1- Abstract Even though the thymus 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 (HCT). 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, with particular emphasis on sex differences with age (SA1); perform studies to better understand the underlying mechanisms governing endogenous thymic regeneration and their breakdown in aged mice, focusing on the balance between inflammatory and pro-regenerative signals from dying cells after acute damage (SA2); and develop therapeutic strategies based on these test known and putative strategies to determine their effectiveness in promoting thymopoiesis in aged tissue at baseline or that has undergone damage (SA3). Our project has multiple points of interaction with the other projects and cores of this P01, including a focus on the hematopoietic and non-hematopoietic stromal microenvironment, regulation of Notch-DLL4 interactions, and of utmost importance, a comprehensive shared sequencing dataset that can be leveraged across the program. Together, these aims and interactions support the overarching goal of the P01 to identify the mechanisms responsible for defects in thymic production of naïve T cells with age and develop methods to improve or reverse them. Therefore, 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.