About the Project
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.
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.
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.
(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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Mathematical Modelling of Neurovascular function: Developing and refining brain tissue models to enable world leading research into neurovascular coupling in health and disease
University of Sheffield