Mechanisms Controlling Thymic, Homeostasis, Involution, and Rebound

整体项目 本计划项目的长期目标是对 调节胸腺上皮细胞（TEC）稳态的细胞和分子机制， TECs在成年胸腺退化中的作用。胸腺是主要的淋巴器官 负责功能性T细胞的产生，因此对于产生和 维持适应性免疫。它也是最早经历显著老化的器官之一- 相关器官退化，称为胸腺退化。胸腺退化导致了一个戏剧性的 新的T细胞的产生下降，是免疫系统中的一个重要因素。 衰老尽管这一主题对人类健康的重要性， 在出生后胸腺中运作并介导胸腺稳态的机制， 对合在很大程度上是未知的。因此，胸腺退化的许多方面都很差， 理解和/或争议。理解机制的相对贡献 这一过程的基础将对改善人类健康产生重大影响。的 拟议的计划项目旨在确定可以 用于诱导胸腺反弹和/或预防退化，重点关注 TEC的变化。这两个项目将测试两个中心假设：1）未能维持 出生后胸腺上皮细胞内稳态是胸腺退化的一种致病机制; 2)Foxnl是TEC发育和维持的关键调节因子， 胸腺退化的主要分子机制。这些假设将通过 三个主要的计划目标，将调查：a）TEC的血统关系 出生后胸腺中的亚群; B）驱动TEC稳态的分子机制;以及c） 这些机制是否是内卷化的原因。这些科学项目有着共同的 确定导致TEC失败的细胞和分子机制的目标 维持胸腺退化。所使用的方法都基于这样一个中心思想， 调节胎儿胸腺发育和TEC分化的机制提供了一个新的途径， 理解胸腺老化和再生的概念框架。个别项目 在P01中，将采用重叠和互补的方法来测试这些假设， 联合收割机的独特的专业知识，实验工具，和机构资源， investigators.

Overall Project The long-term objective of this Program Project is to perform a systematic analysis of the cellular and molecular mechanisms regulating thymic epithelial cell (TEC) homeostasis and the role of TECs in the involution of the adult thymus. The thymus is the primary lymphoid organ responsible for the generation of functional T cells, and is therefore critical for generation and maintenance of adaptive immunity. It is also one of the first organs to undergo significant age- related organ degeneration, termed thymic involution. Thymic involution results in a dramatic drop in the production of new T cells, and is a significant contributing factor in immune senescence. Despite the importance of this subject for human health, the molecular mechanisms that operate in the postnatal thymus and mediate thymic homeostasis and involution are largely unknown. As a result, many aspects of thymic involution are poorly understood and/or controversial. Understanding the relative contributions of the mechanisms underlying this process would have significant implications for improving human health. The proposed Program Project is designed to identify mechanisms and pathways that can be exploited for induction of thymic rebound and/or prevention of involution, focused on the role of changes in TECs. The two projects will test two central hypotheses: 1)that failure to maintain postnatal thymic epithelial cell homeostasis is a causative mechanism in thymic involution; and 2) that down regulation of Foxnl, a pivotal regulator of TEC development and maintenance, is a primary molecular mechanism in thymic involution. These hypotheses will be addressed through three major Program objectives which will investigate: a) the lineage relationships of TEC subsets in the postnatal thymus; b) the molecular mechanisms driving TEC homeostasis; and c) whether these mechanisms are causal for involution. The scientific projects share the common goal of identifying the cellular and molecular mechanisms resulting in the failure of TEC maintenance in thymic involution. The approaches used are all grounded in the central idea that the mechanisms that regulate fetal thymus development and TEC differentiation provide a conceptual framework for understanding thymic aging and regeneration. The individual projects in the P01 will take overlapping and complementary approaches to test these hypotheses that combine the unique expertise, experimental tools, and institutional resources of the investigators.