Grant: Project Grant

The cells' ability to sense and adapt to changes in oxygen level is vital for development and life. A failure to maintain proper oxygen homeostasis is associated with the development of numerous diseases from cardiovascular and chronic pulmonary diseases to cancer. We and others have shown that a major transcription factor called hypoxia-inducible factor (HIF) is targeted for destruction via the concerted actions of an enzyme called prolylhydroxylase (PHD) and the von Hippel-Lindau (VHL) tumour suppressor complex during normal oxygen availability. Under low oxygen levels, HIF accumulates to trigger the expression of various genes such as those that promote anaerobic metabolism, new blood vessel formation, and the production of oxygen-carrying red blood cells to facilitate adaptation and survival in hypoxia. Notably, mutations in VHL cause a rare cancer syndrome called VHL disease, which is characterized by the development of tumours in multiple organ systems as well as a chronic condition called polycythemia where patients produce too many red blood cells. Since the elucidation of the aforementioned evolutionarily conserved oxygen-sensing pathway, individuals with mutations in HIF and PHD have been identified who develop overlapping tumour types with or without polycythemia as observed in VHL patients. We have introduced a classification system to categorize the perplexing clinical manifestations for the emergent HIF-driven and PHD-driven diseases. However, the correlation between specific mutation (genotype) and the varied disease presentation (phenotype) that an individual will develop in their lifetime remains unclear. The present proposal, based on our recent published works and promising preliminary data, aims to unravel the molecular mechanisms underlying these emergent pseudohypoxic diseases as well as by extension the classical VHL disease with important clinical implications in the management of patients with these diseases.