The role of HIF-1α (Hypoxia-inducible factor 1 alpha) for the pathogenesis of psoriasis and related metabolic syndrome

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Psoriasis is one of the most prevalent chronic inflammatory non-communicable skin diseases, affecting around 2% of the world's population. Patients not only suffer from itching, pain and social stigma, but also from associated comorbidities such as inflammatory bowel diseases and metabolic syndrome. Key signaling pathways and their cytokines have been decrypted and led to numerous symptomatic therapies. However, to develop preventive or causative therapeutic approaches, factors that lead to chronic disease and systemic involvement need to be identified. Our unpublished work gives clear hints that the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) is a checkpoint molecule for hallmarks of psoriasis pathogenesis as well as psoriasis-associated comorbidity, however, there is no direct evidence for this concept yet. I put up the hypothesis that after initiation of psoriatic inflammation leading to proliferation of keratinocytes and hypoxia in the epidermis, HIF-1α is activated leading to a) neoangiogenesis b) secretion of proinflammatory cytokines driving recruitment of neutrophils and systemic inflammation and c) a shift of T cell skin infiltrates towards Th17 phenotype, eventually creating the chronic psoriatic phenotype. In the course of this project I want to verify the above proposed hypothesis using histology, cell culture experiments, flow cytometry, murine knock-out models and clinical data from human data bases. The results of this project will increase our knowledge about the central molecular events leading to chronicity of psoriatic inflammation and thus lead to the development of novel drug targets. Collaborating with Professor Randall Johnson, leading a top lab in the field of hypoxia at the Karolinska Institute (KI) and working with Mona Ståhle, senior professor at the Division of Dermatology at KI, I will be able to perform this project in an ideal environment.