Objectives/Aims
.The central hypothesis of this project is that the distinct clinical and catecholamine biochemical phenotypes and gene and protein expression profiles in different types of chromaffin cell tumours reflect development from distinct chromaffin progenitor cells by pathways that offer novel therapeutic targets and markers for diagnosis. This hypothesis will be addressed through the following objectives, with a focus on HIF2a, REST and related secretory and energy pathways.
(I) Take advantage of multicentre clinical protocols, tissue banks and existing microarray and protemomics databases to characterise relationships between hypoxia-angiogenic pathways and catecholamine and mitochondrial energy pathway metabolomes among different groups of paraganglial tumours.
(II) Utilise chromaffin cell model systems to examine mechanistic links and changes in catecholamine metabolomic and secretory phenotypes in relationship to mitochondrial energy and hypoxia-angiogenic pathways after manipulations of key components of the latter pathways.
(III) Identify new tumour biomarkers and pathway targets for therapeutic agents, test utility of biomarkers in banked and prospectively collected biological specimens and initiate studies in chromaffin cell model systems to assess therapeutic efficacy of selected agents against pathway targets.