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Using biomaterials and 3D bioprinting to model the neurovascular unit in dementia


Project Description

Neurovascular dysfunction is a central process in the pathogenesis of Alzheimer’s disease and other dementias. In the brain, cerebrovasculature and neuronal structures are tightly integrated forming the multicellular neurovascular unit comprising endothelial cells, 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, neuroinflammation and neuronal function. Although there is mounting evidence that dysregulation of the neurovascular unit 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 degeneration of the neurovascular unit 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 use novel biomaterials and engineering approaches (specifically 3D bioprinting) to develop models of the neurovascular unit to study what goes wrong in Alzheimer’s disease. These approaches will be combined with the use of patient-specific stem cells made into endothelial cells, astrocytes, microglia and neurons in order to study how the neurovascular unit is altered in disease. The generation of an appropriate 3-dimensional model in which we can modify components of the neurovascular unit will allow us to screen for drugs that correct the dysfunction, and which may have potential to be developed as treatments for Alzheimer’s disease and other dementias.

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.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (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.

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

References

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

Sweeney, M. D., Kisler, K., Montagne, A., Toga, A. W., and Zlokovic, B. V. (2018) The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21, 1318-1331

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

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