The endothelial cell glutamine/glutamate metabolism as a driver for developmental and pathological angiogenesis

The focus of my research proposal is on targeting the glutamine/glutamate metabolism of endothelial cells as a novel avenue for anti-angiogenic therapies in starving tumors from their vascular supply.

Angiogenesis, or the formation of blood vessels, can fuel tumor progression by supplying cancer cells with oxygen and nutrients. Current anti-angiogenic strategies target growth factors to starve tumors from their vascular supply but suffer from limited efficacy and toxicity. I propose to directly target the engine of blood vessel forming endothelial cells (ECs), namely their cellular metabolism onto which angiogenic signals converge. My host lab has recently discovered significant metabolic reprogramming in ECs when they shift from a resting (quiescent) to a proliferating/migrating phenotype during vascular sprouting. Glutamine metabolism is particularly interesting since my preliminary findings show that ECs cannot shift from quiescence to proliferation when starved from glutamine. A multidisciplinary approach including state-of-the-art metabolomics will allow me to determine the metabolic fate of glutamine in ECs and to characterize its importance in vascular branching. I will expand my ongoing phenotypic analysis of mice in which genes involved in glutamine metabolism are deleted in ECs, focusing on glutamine synthetase, given its important link with autophagy. By chemical and genetic targeting of these genes in zebrafish and mouse models, I will study their role in more detail and evaluate their physiological relevance. Finally, I will evaluate the potential of blocking glutamine metabolism as a novel anti-angiogenic therapy.