Heterogeneity of medullary thymic epithelium

胸腺髓质上皮的异质性

• 批准号: 7729248
• 负责人: ANDREW G FARR
• 金额: $ 39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729248
• 关键词: Adult; Aging-Related Process; Candidate Disease Gene; Data; Elderly; Environment; Epithelial; Epithelial Cells; Epithelium; Exhibits; Fibroblast Growth Factor; Foundations; Gene Expression; Gene Targeting; Heterogeneity; Lead; Maintenance; Modeling; Molecular Profiling; Organogenesis; Pattern; Population; Recovery; Regulation; Running; Self Tolerance; Signal Transduction; Specific qualifier value; Staging; Stem cells; Thymic epithelial cell; Thymus Gland; To specify; Work; abstracting; cohort; fetal; immune function; postnatal; progenitor; programs; research study; senescence; transcription factor; young adult

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.

修订后的摘要部分 胸腺上皮的生产性分化对胸腺的生成和建立至关重要 自我容忍的能力。然而，形成胸腺环境的分化程序并不是 很好理解。这里提出的研究旨在为探索一种模式提供基础。 TE的区别与主流观点背道而驰，后者认为TE是一种相当 静态种群；在器官发生早期被指定为胸腺命运的种群，以及 需要Foxn1转录因子完成TE的后规范程序 差异化。我们建议未固定的TE祖细胞在出生后持续存在 胸腺和它们的后代通过动作不断地被指定为胸腺的命运 对Foxn1的影响。根据该模型，Foxn1的瞬时表达定义了一个关键决定 步入TE分化阶段。我们还建议维持前身TE在 出生后的胸腺依赖于成纤维细胞生长因子信号。这里建议进行的实验 将Foxn1定义为胸腺上皮异质性的标志，并将产生分子 我们建议用来代表TE分化的离散早期阶段的TE的轮廓。此外 为筛选Foxn1调控的候选基因靶点，本工作还将为Foxn1调控候选基因靶点的筛选提供实验依据 恢复这一群体胸腺上皮细胞所需的信息 在随后的提案中进行研究。我们的假设是Foxn1+胸腺的调节 上皮细胞亚群集中参与了年龄相关退化的模糊过程。 增强这些潜在的祖细胞存活/扩增的策略可能会导致 以显著增强老年人的胸腺功能。