The Hogan lab, also known as the Vascular Biology lab, investigates the development of lymphatic vasculature and the blood brain barrier, which play important roles in the metastatic spread and treatment of cancer.
Lymphatic vessels play diverse roles in tissue function and disease. Tumour secreted growth factors promote the formation of lymphatics (lymphangiogenesis) and metastasize via new lymphatic vessels. Blocking lymphangiogenesis can reduce metastasis. On the flip-side, new approaches to promote lymphangiogenesis hold promise in lymphoedema, cardiovascular disease and in enhancing immunotherapy in cancer. We characterise new molecules and mechanisms that control lymphangiogenesis using zebrafish, mice and human endothelial models. The Ben Hogan lab uses large scale genetic screens, CRISPR genome editing, single cell genomics and in vivo cell biology.
The blood brain barrier (BBB) separates the brain from circulating blood and macromolecules. The BBB is made up of tightly adherent vascular endothelial cells surrounded by essential mural cell lineages that include pericytes, astrocytes, macrophages and neurons. Together this cellular collaborative known as the neurovascular unit (NVU) determines BBB function. The BBB is essential for brain development and function. The BBB also represents a significant challenge for delivery of therapeutics in brain cancer. The Ben Hogan lab aims to gain fundamental understanding of the regulation of the BBB, towards therapeutic gain. At the Ben Hogan lab, we use large scale genetic screens, live imaging and chemical (drug) screens.
The Ben Hogan lab are using a number of new approaches to model tumour-endothelial cell interactions. Current studies include development of novel anti-lymphangiogenic molecules, large-scale phenotype based drug screening in zebrafish disease models, development of high-throughput brain cancer models and assessment of new methods to promote lymphangiogenesis.
Current work includes analysis of the role of Yap1 and the Hippo pathway in endothelial cell proliferation and expansion of lymphatic networks, the study of alternative pre-mRNA splicing controlled by Nova2 in lymphatic vascular signalling and the analysis of lymphatic endothelial cell fate specification. The Ben Hogan lab are also performing novel chemical (drug) screens using our zebrafish models of disease. Many of our studies converge on the central CCBE1/VEGFC/VEGFR3 pathway, which plays important roles in development and disease.
We are currently undertaking a large scale forward genetic screen using zebrafish to discover genes and molecular mechanisms that control the maturation and function of pericytes and BBB endothelial cells. In addition, we are deveoping new tools towards a drug screening approach to identify molecules that can safely open up the BBB to enhance therapeutics in brain cancer. Brain cancer models are being developed to complement these studies. This work aims to identify new molecular mechanisms and new therapeutic opportunities.
Directly observing key molecules and pathways as they act to control tissue formation, or as they drive pathological phenotypes, is a major challenge in cell biology. We are utilising biosensors that report signalling events and multiple imaging modalities to directly observe real-time molecular functions in cells in normal development and disease models in vivo. This work has uncovered unexpected mechanisms in angiogenesis during wound repair and allowed us to study cell-cell adhesion mechanics in developing tissues. The Ben Hogan lab are currently diversifying our vascular biosensor tools and applying new imaging approaches to observe dynamic changes in individual molecules of interest.
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