Curriculum Neuroscience, Technology and Society, XXXVII series Grant sponsor AIRC Foundation Supervisor Silvio Tosatto Co-Supervisor Alessio Micheli Contact giorgiafrancesca.camagni@phd.unipd.it

Project description
The von Hippel–Lindau (VHL) disease is an human hereditary cancer syndrome characterized by the development of several different benign and malignant tumours (renal cell carcinoma, retinal- and cerebellar-hemangioblastoma, paraganglioma, pheochromocytoma...). VHL disease is caused by the germ-line mutation of the homonymous gene which encodes for a tumour suppressors protein (pVHL). pVHL targets the hypoxia-inducible factor α (HIF-α) protein family, previously hydroxylated by prolyl hydroxylase (PHD) enzymes, for degradation. These enzymes are 2-oxoglutarate-dependent dioxygenases, so hypoxia conditions reduce PHD activity allowing HIF-α to accumulate and translocate to nucleus where it dimerizes with HIF-1β leading expression of various target genes that modulate the hypoxia adaptive changes in cellular metabolism such as angiogenesis. There are three known PHD isoforms encoded by three different genes. They are expressed in all tissues but at different levels and they hydroxylate the HIF-α protein family but with different affinities. PHDs are involved in many biological pathways, in fact they also have HIF-independent functions. For this reason they can be considered not only important pharmaceutical targets for the treatment of hypoxic human disease but can also be considered central regulators of tumor development which, however, is still incompletely understood. Thus, more research is required to obtain a better understanding of the complex mechanisms underlying the effects of hypoxia pathway proteins that are involved in different types of cancer and diseases. Therefore, the main project goal is to characterize the molecular details governing PHDs/substrate recognition through molecular dynamics (MD) simulations. In particular, to identify and characterize their substrate specificity and to understand which inhibitors are best suited to specifically inhibit each PHD isoform. So, this project has a major impact on drug discovery and anti-cancer therapy as well as to shed new light on the molecular details driving the VHL disease.