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Bioengineering stem cells for neuroprotection against stroke


Project Description

"Stroke, in particular ischaemic stroke, is the third major cause of death worldwide and there is significant health impairment in survivors. Estrogen, a steroid hormone is neuroprotective via multiple signalling pathways which include transcription and rapid cell signalling. In animal models, estrogen appears to act via classical estrogen receptors to protect the mitochondria and decrease oxidative stress. In addition, a novel estrogen receptor called GPER1 also confers neuroprotection, possibly by decreasing inflammation. However, the molecular mechanisms by which estrogen is neuroprotective are not completely understood and this knowledge is important to design therapies for stroke.
One of the possible mechanisms is the restoration of neuronal connectivity, achieved by the current medication, tissue plasminogen activator. Again, the exact mechanism remains unknown and would be a valuable contribution to improving stroke outcomes. Our data shows that GPER1 activation and signalling via a novel pathway can increase dendritic spines on neurons. This is directly relevant since dendritic spine changes may change neuronal connectivity, a parameter that is linked to cognitive recovery.
Our long-term objective is to understand the mechanism of estrogen-mediated neuroprotection against stroke and to build a stem cell model that can be used to study how neuroprotection occurs . Based on our preliminary data and literature, we will investigate the role of a novel estrogen receptor, the GPER1 in neuroprotection against stroke,. The student will establish a cell culture model i.e. differentiated human induced pluripotent stem cells (hiPSCs) where chemical insult mimics ischaemic stroke. These differentiated stem cells will consist of both neurons and astrocytes. The student will then explore the contribution of estrogen receptors and their signalling pathways to the reduction of parameters that are associated with stroke such as restoration of neuronal morphology and plasticity. In addition, students who are interested in theoretical modelling and analysis of electrophysiological recordings may also investigate the role of connectivity in neural cultures in recovery from insult. Techniques include primary cell cultures, protein chemistry, electrophysiology, mathematical modelling and microscopy to detect spine density with differentiated stem cells and to relate it to the concomitant changes in neuronal connectivity. The tools for characterising the connectivity automatically will need to be developed and the characteristics of connectivity motifs and their statistic correlating with spine density and the covariation of the two with the ischemic insult, estrogen variation and GPER1 activation will elucidate the protective role of the oestroegen and its putative pathways. This project is at the forefront of stem cell biology and neural cybernetics and is a collaboration between endocrinologists and bioengineers at the School of Biological Sciences. If successful, optimization of such a model will partially refine the use of animal cerebral artery occlusion models and will promote the use of human induced pluripotent stem cells. This project is suitable for students who are interested in either biology or engineering or cybernetics with a view to application in therapeutic medicine and/or personalized medical therapies. The student will be part of a vibrant endocrine and bioengineering group at the University of Reading, with an opportunity to get training in teaching pedagogy. In addition, the student will also have an opportunity to network with several collaborators.
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Funding Notes

Eligibility requirements:

Applications will be considered from any candidate who holds (or expects to obtain) at least a 2:1 or 1st Class Honours Degree or equivalent in a Biology-related or engineering/mathematical subject with an interest in biological questions.

If EU/UK student, please contact Dr. Vasudevan or Dr. Delivopoulos in sufficient time to explore funding options. Informal enquiries to Dr. Vasudevan at or Dr. Delivopoulos at . Primary and secondary supervisors will depend on the candidates strength and focus in this project.


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