Zecchin,A.JPG

Fellow: Annalisa Zecchin, PhD

Institution: Katholieke Universiteit Leuven, Vesalius Research Center

Principal Investigator: Peter Carmeliet, MD, PhD

LF Funding History: FDRS Postdoctoral Fellowship

Hypothesis: We hypothesize that altering nutrient availability can promote lymphatic function to improve lymphedema, and possibly lipedema.

Collaborative Opportunities: Our laboratory is interested in defining metabolic maladaptation of lymphatic endothelial cells in human pathology, with particular focus on lymphedema and lipedema.

To define which metabolic pathways are functionally relevant in distinct disease settings, we aim to profile and study cellular metabolism by using material from preclinical pathological models (mouse) as well as patient samples, for which we seek collaborations with hospital departments. Moreover, (inter)-national collaborations with experts in mouse models of disease will be key in these investigations.

We will apply a multi-disciplinary approach, determining the expression profiling of metabolic enzymes (transcriptomic, RNAseq) in different settings and further confirming the results by metabolic fate analysis via radiolabeled substrate-based metabolic assays and GC-MS and LC-MS analysis of 13C-labeled tracers.

 

 

Project: Novel Metabolite-based Treatment Approach of Lymphedema; Possible Relevance for Lipedema?

Lipedema, the accumulation of lipids within the extremities, is a debilitating disorder whose underlying cause is not understood, and currently has no curative treatments. Lymphedema, the accumulation of fluid in the extremities, is better understood, and has been suggested to be linked to lipedema. In this proposal we will explore whether altering nutrient availability can promote lymphatic function to improve lymphedema, and possibly lipedema.

Acetate supplements recovers lymphangiogenesis (growth of lymphatic vasculature). Lymphatic endothelial cells (LEC) use fatty acid ß-oxidation to proliferate and for epigenetic regulation of lymphatic markers during LEC differentiation. In adult mice, the pharmacological inhibition of fatty acid ß-oxidation by etomoxir impairs lymphatic vessel growth in a corneal model of injury-induced lymphangiogenesis. Importantly, the elevation of plasma acetate rescues this defect and restores lymphangiogenesis in etomoxir-treated mice to levels observed in vehicle-treated controls. Figures a-c, Corneal cauterization-induced injury in WT mice treated with vehicle (ctrl), acetate only (ac), etomoxir only (eto), or etomoxir + acetate (eto+ac). a, LYVE1⁺ lymphatic outgrowth (green). CD31 immunostaining (red) highlights blood vessels, and also weakly stains lymphatic vessels. Scale bars: 500 µm. b,c, Lymphatic vessel outgrowth area and branch point density. Images courtesy of Annalisa Zecchin and Peter Carmeliet, KU Leuven, and were published in Wong et al, Nature 2017; doi:10.1038/nature21028.

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