Neurovascular dysfunction is a central process in the pathogenesis of Alzheimer’s disease and other dementias. In the brain, vascular and neuronal structures are tightly integrated forming the multicellular neurovascular unit comprising endothelial cells, pericytes, astrocytes, microglia and neurons. Complex and dynamic interactions between these cells and the surrounding extracellular matrix shape neuronal, vascular and inflammatory function both in health and disease. The neurovascular unit is central to the regulation of cerebral blood flow, blood-brain barrier function and neuronal function. Although there is mounting evidence that neurovascular dysfunction leads to neurodegenerative conditions, the precise molecular mechanisms underlying this failure are unclear. We hypothesise that abnormalities in the cells of the neurovascular unit and in the surrounding extracellular matrix are causatively related to the neurovascular dysfunction in Alzheimer’s disease and other dementias. Understanding the molecular and cellular mechanisms that underpin the interactions between the various components of the neurovascular unit and how these malfunction in Alzheimer’s disease and other dementias is a key knowledge gap. In this project the student will combine biomaterial and engineering approaches (e.g. 3D bioprinting) with the use of induced pluripotent stem cells differentiated into endothelial cells, pericytes, astrocytes, microglia and neurons in order to study how the neurovascular unit is altered in disease. Opportunities to use the model to screen for drugs that correct neurovascular dysfunction, and which may have potential to be developed as treatments for Alzheimer’s disease and other dementias, will be explored.
Training/techniques to be provided:
The student will receive training in the growth, differentiation and phenotypic characterisation of induced pluripotent stem cells to endothelial cells, pericytes, astrocytes, microglia and neurons, as well as in measurements of cell proliferation and viability, expression of appropriate markers, functional assays, including transendothelial resistance measurement. Training in the use of confocal immunofluorescence microscopy and other advanced microscopy techniques will be provided through the Faculty’s Core Facility. The student will receive full training in generation of hydrogels and in state of the art 3D Bioprinting for the production of tissue models with discrete and/or continuous gradients. He/she will also have access to our core facilities for mechanical, morphological and chemical characterization of materials and scaffolds.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (B.Sc. or equivalent) in a related area / subject (e.g. biochemistry, cell biology, neuroscience, biomaterials) and preferably a master degree in a related area. Candidates with experience in mammalian cell biology or use of biomaterials are encouraged to apply.
For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk
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Jarosz-Griffiths, H.H., Corbett, N.J., Rowland, H.A., Fisher, K., Jones, A.C., Baron, J., Howell, G.J., Cowley, S.A., Chintawar, S., Cader, M.Z., Kellett, K.A.B. & Hooper, N.M. (2019) Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers. J. Biol. Chem. 294, 7085-7097.
Potjewyd, G., Moxon, S., Wang, T., Domingos, M., and Hooper, N. M. (2018) Tissue Engineering 3D Neurovascular Units: A Biomaterials and Bioprinting Perspective. Trends Biotechnol 36, 457-472
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Raphael, B., Khalil, T., Workman, V.L., Smith, A., Brown, C.P., Streuli, C., Saiani, A. & Domingos, M. (2017) 3D cell bioprinting of self-assembling peptide-based hydrogels, Materials Letters, 190, 103-106