Differentiation programs of thymic epithelium

资助号：1R01AI081811-01 胸腺上皮的生产性分化是胸腺生成的关键，而 建立自我宽容。然而，形成 胸腺环境还不是很清楚。这里提出的研究意在测试一个 共同构成运行的TE差异化模型的假设数量 与主流观点相反，该观点认为TE是一个相当稳定的人口； 一种在器官发生早期被指定为胸腺命运的生物，它需要 FOXN1转录因子完成TE的后规范程序 差异化。我们建议未分离的TE祖细胞持续存在于 出生后的胸腺和他们的后代继续被指定为胸腺的命运 通过Foxn1的行动。根据该模型，Foxn1的瞬时表达 确定了TE区分中的关键决定步骤。我们亦建议， 祖细胞和/或未成熟TE在出生后胸腺中的维持依赖于 成纤维细胞生长因子信号转导。这里提出的实验将评估 这一信号通路在TE分化中的变化并确定 我们建议代表的TE的发展潜力和分子图谱 TE分化的离散早期阶段。对该信号通路的干扰可能 促进与年龄相关的退化现象，同时刺激这一途径 可能导致鉴定不同群体的TE祖细胞具有独特的 具有发展潜力，可能具有重要的临床价值。

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.