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)动态平衡的细胞和分子机制 TECs在成人胸腺退缩中的作用。胸腺是主要的淋巴器官 负责产生有功能的T细胞，因此对产生和 维持获得性免疫。它也是最早经历显著年龄变化的器官之一- 相关器官变性，称为胸腺退行性变。胸腺退化导致戏剧性的 新T细胞的产生减少，是免疫中的一个重要因素 衰老。尽管这一主题对人类健康很重要，但分子 作用于出生后胸腺并调节胸腺动态平衡的机制 退化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/或有争议的。了解这些机制的相对贡献 这一过程的基础将对改善人类健康产生重大影响。这个 建议的计划项目旨在确定可以 被用来诱导胸腺反弹和/或防止退缩，重点是 TEC的变化。这两个项目将检验两个核心假设：1)未能维持 出生后胸腺上皮细胞动态平衡是胸腺退化的一种机制； 2)下调Foxn1是TEC开发和维护的关键调节因子，是一种 胸腺退化的主要分子机制。这些假设将通过 将调查的三个主要计划目标：a)TEC的血统关系 出生后胸腺的亚群；b)驱动TEC动态平衡的分子机制；以及c) 这些机制是否是内卷化的原因。这些科学项目有共同之处 确定导致TEC失败的细胞和分子机制的目标 胸腺退化的维持。所使用的方法都植根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 理解胸腺衰老和再生的概念框架。个别项目 将采取重叠和互补的方法来检验这些假设 将独特的专业知识、实验工具和机构资源结合起来 调查人员。

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.