Heterogeneity of medullary thymic epithelium

修订摘要部分 胸腺上皮的生产性分化对于胸腺生成和胸腺细胞的建立至关重要。 自我宽容。然而，形成胸腺环境的分化程序不是 很好理解。本文提出的研究旨在为探索 与主流观点背道而驰的TE差异，认为TE是一个相当好的 静态种群;一个在器官发生早期被指定为胸腺命运的种群， 需要Foxn 1转录因子来完成TE的后特化程序 分化我们认为未定型的TE祖细胞在出生后持续存在， 胸腺和他们的后代不断被指定为胸腺的命运，通过行动， 关于Foxn 1根据这个模型，Foxn 1的瞬时表达定义了一个关键的决定因素， TE差异化步骤。我们还建议，祖细胞TE的维持， 出生后胸腺依赖于成纤维细胞生长因子信号传导。这里提出的实验 将Foxn 1定义为胸腺上皮异质性的标志物，并将产生分子生物学效应。 TE的轮廓，我们建议代表离散的早期阶段TE分化。此外 对于Foxn 1调控的候选基因靶点的鉴定，这项工作也将提供 恢复该胸腺上皮细胞群体的功能所需的信息 在随后的研究中。我们的假设是，这种Foxn 1+胸腺细胞的调节 上皮细胞亚群主要参与年龄相关性退化的不明确过程。 增强这些潜在祖上皮细胞的存活/扩增的策略可能导致 显著增强老年人的胸腺功能。

Revised Abstract Section Productive differentiation of thymic epithelium is critical for thymopoiesis and the establishment of self-tolerance. However, the differentiation program that forms the thymic environment is not well understood. Studies proposed here are intended provide the foundation to explore a model of TE differentiation that runs counter to the prevailing view, which has considered TE to be a fairly static population; one that is specified early during organogenesis to a thymic fate and one that requires the Foxn1 transcription factor to complete the post-specification program of TE differentiation. We are proposing that uncommitted TE progenitor cells persist in the postnatal thymus and that their progeny are continually being specified to a thymic fate through the action of Foxn1. According to this model, transient expression of Foxn1 defines a critical determining step in TE differentiation. We also propose that the maintenance of progenitor TE in the postnatal thymus is dependent on fibroblast growth factor signaling. Experiments proposed here will define Foxn1 as a marker of thymic epithelial heterogeneity and will generate molecular profiles of TE that we propose to represent discrete early stages of TE differentiation. In addition to the identification of candidate gene targets of Foxn1-regulation, this work will also provide the information required for the recovery of this population of thymic epithelial cells for functional studies in subsequent proposals. It is our hypothesis that regulation of this Foxn1+ thymic epithelial subset is centrally involved in the ill-defined process of age-related involution. Strategies to enhance the survival/expansion of these potential progenitor epithelial cells may lead to significantly enhanced thymic function in the elderly.