Zebrafish models of vascular disease: lymphatic malformation

Summary Lymphatic malformation (also known as lymphangioma) is a rare childhood disease caused by uncontrolled proliferation of the lymphatic endothelium. These malformations are typically present at birth, or soon after, and are largely treated with surgery when possible. The genetic causes of lymphangioma remain to be fully understood but somatic mutations in PIK3CA, impacting the AKT-mTOR pathway, have emerged as causative in many cases. Several potential molecular therapies have been proposed but their relative utilities remain to be fully assessed. The project will generate genetic, inducible, models of lymphangioma in zebrafish and attempt to generate CRISPRinduced models. These will drive vascular malformation by expression of mutant PIK3CA expression. Phenotype will be assessed with molecular markers and confocal imaging. The models generated will ultimately be used to assess the efficacy of a series of candidate therapeutic molecules. The project will employ transgenesis, pharmacology, liveimaging of development (confocal) and molecular biology approaches.

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