The role of the von Hippel-Lindau Hypoxia-inducible factor (VHL-HIF) pathway in cardiac and skeletal muscle energetics. (360G-Wellcome-090123_Z_09_Z)

This project aims to investigate the metabolic phenotype in mice engineered to have the Chuvash Polycythemia mutation. This is interesting because the Chuvash mutation causes a modest elevation in the hypoxia inducible factor family of transcription factors, and this enables us to study the effects of hypoxia signalling on metabolism without the confounding influence of actual periods of low oxygen availability. As yet unpublished observations in humans have shown a profound effect of Chuvash po lycythemia on metabolism which requires further dissection in an animal model. Our specific aims are: a) to establish whether a similar phenotype exists in the mice; b) to determine whether the predicted alterations in enzyme concentrations/activities occur in these mice; c) to determine whether there is a significant alteration of pyruvate metabolism (with a switch away from entry to the TCA cycle towards lactate production) and d) to determine whether the substrate switching observed in the fa iling (chronically hypoxic) heart is also induced in these mice. The results from these studies should provide some fundamental insights into the regulation of metabolism together with a better understanding of the degree to which alterations in HIF may underlie the metabolic changes in the failing heart.