Characterising blood-brain barrier formation and function using zebrafish to understand human vascular hyperpermeability

   School of Life Sciences

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  Dr R Wilkinson, Dr M Gering  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The blood-brain barrier (BBB) is a highly selectively permeable network of blood vessels within the brain. This barrier is essential for central nervous system (CNS) homeostasis by controlling molecular flux between the blood and the brain and protecting it from pathogens and toxins. Selective permeability of the BBB is controlled by the presence of endothelial tight junctions and supportive non-endothelial mural cells which limit vascular permeability. Unusually low levels of vesicle trafficking at the BBB recently led to identification of genetic programs which establish a functional barrier by inhibiting the ability of molecules to be transported across blood vessels within the brain by a process known as transcytosis. This indicates that the cells which form blood vessels in the brain possess a developmental programme which actively suppresses transcytosis during BBB formation. Abnormal BBB permeability is involved in the pathogenesis of stroke and neurodegenerative conditions including Alzheimer’s. We have only limited knowledge of the basic biology underlying development of BBB permeability, and the real-time dynamics of BBB permeability are unknown. This project will characterise the genetic mechanisms and cell signalling pathways responsible for establishing and controlling the permeability of the blood brain barrier.

We use zebrafish to study how networks of blood vessels develop and how their permeability is controlled because zebrafish embryos are optically translucent and develop outside of the parent. This allows us to label blood vessels fluorescently and directly observe leaky blood vessels in zebrafish embryos using a microscope. In zebrafish, the BBB is quickly established by 72 hours post fertilisation and importantly, mechanisms which regulate blood vessel formation and function in zebrafish are highly conserved with humans. We use advanced light sheet fluorescence microscopy and confocal microscopy to image leaky blood vessels in zebrafish embryos and employ RNA-Sequencing to identify molecular candidates which may control vessel permeability. We also employ cutting edge CRISPR/Cas9 and CRISPR interference technologies developed within our group to test candidate genes and pathways.

Projects will be based in the Wilkinson lab within the Medical School, Queen’s Medical Centre, University of Nottingham, a friendly and dynamic group embedded in a wider cohesive group of developmental and molecular biologists in the School of Life Sciences

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