Kazuhide Shaun Okuda group

Lymphoedema is a disease associated with excessive tissue swelling. When left untreated lymphoedema symptoms can worsen, leading to decreased mobility, chronic pain and increased risk of potentially lethal infection. Primary lymphoedema (caused by genetic mutation) is currently incurable, and current treatment options only address the symptoms of the disease. While several surgical treatment options exist for secondary lymphoedema (acquired through lymphatic trauma), data on patient outcomes are still limited, as surgical approaches are highly personalised to each case and outcomes can be highly unpredictable.

Using cutting-edge methodologies in zebrafish, we seek to understand the mechanisms that drive or inhibit lymphatic regeneration to reveal therapeutic targets for stimulating lymphatic regeneration. We are also using various in vivo (zebrafish) screening approaches to identify pro-lymphangiogenic therapies that will be tested on our zebrafish lymphoedema models.

We have a strong track record of using the zebrafish model to identify novel mechanisms of (lymph)angiogenesis. These mechanisms could be targeted to inhibit pathological lymphatic/blood vessel growth in human diseases. We are particularly interested in RNA helicase DDX21, which we recently found to be selectively required for lymphatic development in zebrafish. We are now investigating the mechanisms that drive this selectivity.

We are also conducting drug screens in zebrafish to identify promising anti-(lymph)angiogenic small molecules. We have already identified several promising leads including 3,4-Difluorobenzocurcumin and Canthin-6-one. The mechanism of action of these leads will be elucidated to potentially identify novel therapeutic targets for anti-(lymph)angiogenic therapy. We are also testing whether these leads could be novel therapies for lymphatic malformations and cancer.

The optical transperency of zebrafish embryos and larvae allows for the live-imaging of the development, function, regeneration, and pathology of blood and lymphatic vessels at unprecedented resolution. We have developed zebrafish biosensor transgenic lines that enable real-time visualisation of important signalling activities in blood and lymphatic endothelial cells such as ribosome biogenesis and Erk signalling. We are developing new biosensor zebrafish transgenics that enable visualisation andquantification of other signalling activities in endothelial cells. We will use these biosensor transgenics to elucidate dynamic mechanisms that drive vascular development, maintenance, and regeneration.