Unravelling the role of ketone body oxidation in lymphagiogenesis

Not much is known about the metabolic mechanism of the lymphangiogenesis (the growth of the lymphatic vessels). According to recent discovery, the fatty acid oxidation (FAO)-derived acetyl-CoA in lymphatic endothelial cells (LECs - the cells lining the lymphatic vessels) is related to this process. Blocking FAO in LECs causes lymphangiogenesis defects and subdermal lymphedema. Since no lymphedema treatment is available, I will investigate if the dietary administration of ketone bodies or a ketogenic diet, which is the sources of acetyl-CoA, will stimulate lymphagiogenesis in a lymphedema therapy. First, I will explore the precise role of the ketolysis rate-limiting enzyme Oxct1 in LECs both in vitro and in mouse models. Then, I will use state-of-the-art single cell RNA sequencing (scRNA-seq) in order to compare the metabolic shifts caused by the ketone body supplementation in LECs of mouse skin samples, in health and in disease (lymphedema). scRNA-seq analysis of dermal LECs from lymphedema patients will be a useful method to identify the metabolic targets that might be valuable for designing better tailored therapeutic strategies. With the promising unique novel insight on LEC markers and genes in lymphatic vessel disease and response to ketogenic diet, this project is certainly feasible and has a great translational potential.