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

项目2：老化胸腺对损伤和再生的反应 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，如细胞减少性化疗或放疗，它也有显着的能力， 进行内源性修复然而，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。 接受免疫损伤的患者，例如由常见的癌症细胞减少疗法引起的， 造血干细胞移植（HSCT）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， 与年龄相关的胸腺退化。我们将比较和对比我们所知道的 细胞和分子途径，支持胸腺再生在年轻的动物，以再生 在正常胸腺老化过程中小鼠的反应;并制定合理的干预策略，以改善 老年小鼠的再生。在本项目中，我们将全面评估内源性再生 寿命反应（SA 1），进行研究，以更好地了解潜在的机制， 内源性胸腺再生及其在老年小鼠（SA 2）中的破坏，并测试已知和假定的 策略，以确定它们在促进已经经历了老化的组织中的胸腺生成中的有效性。 损伤（SA 3）。 我们的项目与本P01的其他项目和核心有多个交互点，包括提供 为探讨内皮细胞（EC）和BMP 4在胸腺和SLO衰老中的作用奠定基础。所有这些 目的支持P01的总体目标，即确定胸腺缺陷的机制。 随着年龄的增长产生幼稚T细胞。概述的机制和临床前研究有可能 定义胸腺再生的重要新途径，这可能导致临床方法， 增强由于年龄相关退化而导致胸腺大量减少的患者的T细胞免疫力。

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.