THYMIC ENVIRONMENT AND T CELL DIFFERENTIATION

描述(改编自调查者摘要)：明显不同 胸腺上皮细胞(TE)群支持不同方面的 胸腺细胞发育，皮质TE有助于胸腺细胞前扩张 和正选择，以及延髓TE参与负选择。 这种TE异质性的基础是，调节 建立功能和形态截然不同的上皮细胞 隔间定义不明确，其相互作用的性质 胸腺细胞仍然知之甚少。这里提出的研究将考察两个 胸腺环境的相关方面：第一，选定的成员 成纤维细胞生长因子家族深刻影响血管内皮细胞 TE亚群的生长/分化和第二，作为胸腺内的来源 这些介质，胸腺细胞直接影响这些过程。后者 假说可以解释胸腺结构的变化。 在胸腺细胞分化受阻的小鼠模型中观察到。研究 将提供有关以下内容的新信息 部分成纤维细胞生长因子家族成员及其受体的时空分布 在胸腺环境中识别这些配体，并识别细胞 胸腺内这些介质的来源。其他研究将定义 FGFs的功能活性对表型和功能的影响 TE细胞系和原代TE培养物的特性及其对表型和 胎儿胸腺器官培养的功能完整性。几个突变体和 这些FGFs水平改变或带有显性阴性的转基因小鼠 各种形式的成纤维细胞生长因子受体也将被用来检验这一假设。 了解胸腺细胞和TE之间的相互作用 胸腺上皮细胞异质性的发展和维持 淋巴生成环境具有重要的临床相关性，并可能导致 治疗方式将有利于逆转 影响T细胞产生的原发或获得性免疫缺陷。在……里面 此外，这些信息可能有助于我们理解潜在的机制 与年龄相关的胸腺衰老和设计延缓年龄相关的方法 胸腺功能丧失。

DESCRIPTION (Adapted from the Investigator's abstract): Phenotypically distinct populations of thymic epithelial cells (TE) support different aspects of thymocyte development, with cortical TE contributing to pro-thymocyte expansion and positive selection, and medullary TE participating in negative selection. The basis for this TE heterogeneity, the interactions that mediate the establishment these functional and morphologically distinct epithelial compartments are ill defined and the nature of their interactions with thymocytes remain poorly understood. Studies proposed here will examine two related aspects of the thymic environment: first, that selected members of the fibroblast growth factor (FGF) family profoundly affect the growth/differentiation of TE subsets and second, as an intrathymic source of these mediators, thymocytes directly affect these processes. This latter hypothesis would account for the alterations in the thymic architecture observed in murine models where thymocyte differentiation is arrested. Studies proposed in this application will provide new information regarding the temporal and spatial patterns of selected FGF family members and the receptors for these ligands within the thymic environment and identify the cellular source of these mediators within the thymus. Other studies will define the effects on the functional activity of FGFs on phenotypic and functional properties of TE cell lines and primary TE cultures and on the phenotype and functional integrity of fetal thymus organ cultures. Several mutant and transgenic mice with altered levels of these FGFs or bearing dominant-negative forms of the FGF receptor will also be used to test this hypothesis. Understanding the interplay between thymocyte and TE that regulate the development and maintenance of thymic epithelial heterogeneity and hence the lymphopoietic environment has important clinical relevance and may lead to therapeutic modalities that would be beneficial in reversing the effects of primary or acquired immunodeficiencies affecting T-cell production. In addition, the information may help us understand mechanisms underlying age-related thymic senescence and to design approaches to retard age-related losses of thymic function.