Differentiation programs of thymic epithelium

授权编号：1 R 01 AI 081811 - 01主要研究者姓名：FARR，ANDREW G 胸腺上皮的生产性分化对于胸腺生成至关重要， 建立自我宽容。然而，形成差异化方案的 胸腺的环境还不清楚。这里提出的研究旨在测试 共同构成TE分化模型的假设数量， 与主流观点相反，主流观点认为TE是一个相当静态的群体; 一种在器官发生早期被指定为胸腺命运的基因， Foxn 1转录因子完成TE的后特化程序 分化我们提出，未定型的TE祖细胞持续存在于 出生后胸腺和他们的后代不断被指定为胸腺的命运 通过Foxn 1的作用。根据该模型，Foxn 1的瞬时表达 定义了TE差异化的关键决定步骤。我们亦建议 出生后胸腺中祖细胞和/或未成熟TE的维持依赖于 成纤维细胞生长因子信号传导。本文提出的实验将评估 这种信号通路的改变对TE分化的影响，并确定 发展潜力和分子概况的TE，我们建议代表 TE分化的离散早期阶段。干扰这种信号通路可能 有助于与年龄相关的退化现象，而刺激这一途径 可能导致鉴定不同群体的TE祖细胞， 可能具有重要的临床应用价值。

Grant Number: 1R01AI081811 - 01 PI Name: FARR , ANDREW G 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 to test a number of hypotheses that collectively constitute 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 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 and/or immature TE in the postnatal thymus is dependent on fibroblast growth factor signaling. Experiments proposed here will evaluate the impact of alterations of this signaling pathway on TE differentiation and determine the developmental potential and molecular profiles of TE that we propose to represent discrete early stages of TE differentiation. Interference with this signaling pathway may contribute to the phenomenon of age-related involution, while stimulation of this pathway may lead to the identification of different populations of TE progenitor cells with unique developmental potentials and may have important clinical value.