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MRC DiMeN Doctoral Training Partnership: Two diseases, one brain: The effects of cardiovascular disease on the speed, progression and severity of Alzheimer's Disease


   MRC DiMeN Doctoral Training Partnership


Sheffield United Kingdom Neuroscience Physiology

About the Project

By 2025, in the UK alone, over 1 million people are expected to be living with dementia, for which there is currently no effective treatment. The most common dementia is Alzheimer’s disease. Growing evidence suggests that early in Alzheimer’s disease brain blood flow is reduced and neurovascular coupling - which regulates the supply of oxygen and glucose to active brain regions - is dysfunctional. This neurovascular breakdown has been suggested to lead to neuronal death and cognitive deficits.

Contrary to existing literature, we recently demonstrated that neurovascular coupling was largely unaltered at key timepoints in disease development in a mild preclinical model of Alzheimer’s disease. In this mild model, therefore, neurovascular deficits may be more subtle than predicted.

In human Alzheimer’s disease, cerebrovascular and cardiovascular dysfunction often occur together but are treated separately. However, a compromised peripheral vascular physiology may have modifying effects on central neurovascular function. In this project, we will combine pre-clinical models of Alzheimer’s disease with a novel model of atherosclerosis (ATH) to understand how cardiovascular disease affects cerebrovascular health. The findings will increase our knowledge of how neurovascular dysfunction contributes to neurodegenerative conditions and how cardiovascular disease might affect the progression of Alzheimer’s disease.

To investigate which cellular changes in the neurovascular unit contribute to Alzheimer’s disease pathology throughout the lifecourse in preclinical models of Alzheimer’s disease with and without ATH, we will employ high-resolution 2-photon imaging to measure cellular calcium and cerebral blood flow. Understanding which cells of the neurovascular unit are failing in novel mixed models of Alzheimer’s disease and ATH will potentially lead to new therapeutic targets in humans. To assess Alzheimer’s disease progression, and how it is impacted by ATH, cognitive function will be assessed with behavioural testing and immunohistochemical approaches will further elucidate pathology underlying any observed neurovascular dysfunction. During the PhD you will also be trained in the advanced computational (e.g. MATLAB) and statistical skills necessary for data analysis.

This project will further our understanding of how, and when, neurovascular dysfunction contributes to Alzheimer’s disease progression and combine preclinical models of Alzheimer’s disease with a novel model of ATH to study how cardiovascular disease might affect Alzheimer’s disease progression.

https://www.sheffield.ac.uk/psychology/people/research/clare-howarth

https://www.sheffield.ac.uk/psychology/people/academic/jason-berwick

https://www.sheffield.ac.uk/medicine/people/iicd/sheila-francis

@nvc_sheffield

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

http://www.dimen.org.uk/how-to-apply/application-overview


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover UK tuition fees, stipend and project costs as standard. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2022
Good luck!

References

Sharp PS et al. Neurovascular coupling preserved in a chronic mouse model of Alzheimer's disease: Methodology is critical. J Cereb Blood Flow Metab. 2020 Nov;40(11):2289-2303. doi: 10.1177/0271678X19890830.
https://eprints.whiterose.ac.uk/153114/
Howarth C et al. A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. J Neurosci. 2017 Mar 1;37(9):2403-2414. doi: 10.1523/JNEUROSCI.0005-16.2016.
https://eprints.whiterose.ac.uk/109756/
Gomez D et al. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med. 2018 Sep;24(9):1418-1429. doi: 10.1038/s41591-018-0124-5.
https://eprints.whiterose.ac.uk/137040/

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