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

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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 Within unpublished preliminary experiments we were able to show that within TECs the central negative regulator of the hypoxic-response-pathway, the von Hippel-Lindau protein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.