The role of the hypoxic-response-pathway in thymic epithelial cells for thymic development, function and recovery from antineoplastic therapy

在胸腺内，t细胞由造血祖细胞在由胸腺上皮细胞（TECs）组成的高度特化的缺氧微环境中发育而来。因此，TECs内普遍存在的缺氧反应通路可能对胸腺的正常发育和功能起重要作用。因此，我们计划通过使用条件等位基因和Foxn1-Cre转基因对体内tec内缺氧反应途径的核心成分进行遗传修饰。在未发表的初步实验中，我们能够证明在tec中，缺氧反应途径的中心负调节因子von Hippel-Lindau蛋白（pVhl）对胸腺发育至关重要。在tec特异性vhl缺失的胚胎中，胸腺是基本的，而在成年小鼠中，胸腺完全缺失。本研究旨在阐明这种胸腺发育不全的机制。此外，我们将在tec中删除缺氧诱导因子-1alpha和-2alpha，以研究它们对胸腺发育和功能的影响。tec易受放射和化疗药物的影响。然而，它们有再生的能力。缺氧诱导因子在各种器官系统的再生过程中发挥核心作用，并能够介导对照射和化疗药物的抗性。因此，我们计划分析tec特异性基因缺氧诱导因子修饰对照射和化疗暴露后胸腺再生的影响。最后，我们打算研究缺氧反应途径的药理学调节是否介导对tec的放射和化学保护作用以及对胸腺再生的积极作用。

Inside the thymus T-cells develop from hematopoietic progenitors within a highly specialized hypoxic microenvironment consisting of thymic epithelial cells (TECs). Therefore, the ubiquitous hypoxic response pathway within TECs might play an important role for the normal development and function of the thymus. Accordingly, we plan to genetically modify central components of the hypoxic response pathway within TECs in vivo by using conditional alleles and the Foxn1-Cre transgene. Within unpublished preliminary experiments we were able to show that within TECs the central negative regulator of the hypoxic-response-pathway, the von Hippel-Lindau protein (pVhl), is essential for thymic development. In embryos with a TEC-specific Vhl-deletion the thymus was rudimental while in adult mice it was completely absent.The proposed study aims to elucidate the mechanism of this thymic aplasia. Moreover, we will delete hypoxia-inducible factors-1alpha and -2alpha within TECs in order to investigate their impact on thymic development and function. TECs are susceptible to irradiation and chemotherapeutic agents. However, they are capable of regeneration. Hypoxia-inducible factors play a central role in regenerative processes in various organ systems and are able to mediate resistance towards irradiation and chemotherapeutic agents. Therefore, it is planned to analyze the impact of TEC-specific genetic hypoxia-inducible factor modification on thymic regeneration post irradiation and chemotherapy exposure. Finally, we intend to examine whether the pharmacologic modulation of the hypoxic-response-pathway mediates a radio- and chemoprotective effect on TECs and a positive effect on thymic regeneration.