ºÚÁÏÉç

Supervisors: Dr Helen Stolp, Dr Dong Xia and Prof Caroline Wheeler-Jones

Department: Comparative Biomedical Sciences

Project Details

Vascular dysfunction is recognized as contributing to the etiology of neurological, and particularly neurodegenerative, disorders. Genetic risk factors have been identified for neurodegenerative disorders, but there is substantial variation in age of onset, severity, recovery/speed of decline experienced by patients that is not fully explained by known factors. We hypothesise that these are determined by life events that add stress to the cerebrovascular system, affecting repair responses and the specific burden of risk in each individual. In a healthy brain, the process of neurovascular coupling ensures blood flow that meets the metabolic demands of the brain. In early life and mild injury, compensatory and repair processes protect the brain, but these compensatory mechanisms decrease in effectiveness with ageing. We propose this decreased compensatory capacity may be accelerated in individuals with genetic susceptibility to neurodegeneration specifically when the genetic differences are in genes involved in mechanisms of vascular compensation and repair. Our recent bioinformatic analysis has identified key injury signaling pathways common to vascular dysfunction that may initiate cerebrovascular stress and alter neurodegenerative risk. However, the signaling pathways responsible for recovery, or lack thereof, are less well elucidated.

The aim of this work is to identify common pathways for vascular repair that could be affected by specific genetic risk, prolonging vascular dysfunction and increasing susceptibility of neurodegenerative disease. This project will utilize publicly available RNASeq data from published studies showing the transcriptional response of brain endothelial cells days to weeks following injury. Differentially expressed genes will be identified and clustered using hierarchical clustering, followed by functional enrichment and pathway analysis. Gene lists will be refined on the basis of known protein interactions, druggable targets and cross-matching with known neurodegenerative risk factors. Finally, findings will be validated by immunohistochemistry using existing tissue banks. These data will be used in the future to identify disease risk factors and potential therapeutic targets for neurodegenerative disease.

References

1. Kisler, K., Nelson, A., Montagne, A. et al. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18, 419–434 (2017)

2. Knox EG, Aburto MR, Clarke G, Cryan JF, O'Driscoll CM. (2022) The blood-brain barrier in aging and neurodegeneration. Mol Psychiatry. 27(6):2659-2673.

3. Kodali MC, Chen H, Liao FF. (2020) Temporal unsnarling of brain’s acute neuroinflammatory transcriptional profiles reveals panendothelitis as the earliest event preceding microgliosis. Mol Psychiatry. 26, 3905–3919.

Requirements

Essential:

• Must meet our standard MRes entry requirements.

• Must have a BSc or equivalent degree in neuroscience or a related field of biological sciences. 

Desirable:

• Good organizational skills and enthusiasm.

• Prior experience with computational modeling or bioinformatics is desirable. 

This is a full time project commencing in October 2023, based at ºÚÁÏÉç's Camden campus.

Funding

Partially funded: e.g. the lab will be covering the project costs, with the MRes student expected to meet the course fees and their living expenses.

International applicants are welcome to apply but must be able to fund the difference between "Home" and "Overseas" tuition fees.

You can find information on fees and funding online. A postgraduate master's loan may be available to help cover costs.

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Deadline: 30^th July 2023

We welcome informal enquiries - these should be directed to Helen Stolp (hstolp@rvc.ac.uk)

Interview date and location: TBC (August 2023)