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(BHF Acc) Hypertension and the Brain: How does neurovascular uncoupling lead to small vessel disease?


Faculty of Biology, Medicine and Health

About the Project

The project will principally employ two techniques at the technological cutting edge of neurovascular physiology: the ex – vivo Capillary – to – Arteriolar preparation (CaPa prep – see reference 2) and in – vivo imaging of cerebral blood flow using two photon microscopy via a cranial window in mice. Acquisition of these two techniques give unparalleled information into microcirculatory function in the brain and can precisely identify the cellular defects underlying hypertension induced vascular dementia.

For the project we propose to use an established mouse model of hypertension, the BPH-2 mouse. This mouse has polygenic hypertension, similar to the human phenotype and also develops late life cognitive impairment and white matter hyperintensities. As part of our neurovascular consortium, we have these mice and have pilot data to indicate that there is neurovascular uncoupling, as evidenced by the presence of alterations in blood flow, assessed using transcranial ultrasound, in response to whisker stimulation. Precisely at which point in the development of hypertension that neurovascular uncoupling occurs and the cellular mechanisms underlying this deficit are not known and are of course crucial questions to be answered in the development of a new therapeutic strategy.

Using both normotensive mice (BPN) and anti – hypertensive treated BPH2 mice as controls, we will study the progression of microvascular dysfunction and neurovascular coupling at specific time points during the first year of life of the mouse (i.e. into old age and correlating with neurological symptoms). We will also study Pharmacological approaches to manipulate the principal ion channels involved in neurovascular coupling (Inward rectifier K+, large conductance calcium activated K+, TRPV4) will elucidate the microvascular pathways by which neurovascular coupling occurs from the perspective of the microcirculation. We will also use a late – adult (i.e. from six months onward) administration of amlodipine for the BPH2 mice to see whether this has any effect on subsequent neurovascular coupling. This protocol most commonly mimics the human condition.


Entry Requirements:
Applications are invited from UK/EU nationals only. Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.

Funding Notes

This project is to be funded under the BHF Accelerator Award. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BHF Accelerator Award website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden JE, Hill-Eubanks D, Nelson MT. Nat Neurosci. 2017 May;20(5):717-726. doi: 10.1038
(article detailing potassium channel in neurovascular coupling)

https://www.jove.com/video/60676/ex-vivo-pressurized-hippocampal-capillary-parenchymal-arteriole (JOVE article and video detailing preparation of Capillary to arteriolar preparation)


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