From bedside back to bench: understanding why renal nerve activity is so important for controlling blood pressure. Medical Studies, PhD (GW4 BioMed MRC DTP)

Supervisory team:
Professor Angela Shore, University of Exeter Medical School
Dr Maarten Koeners, University of Exeter Medical School
Dr Mino Belle, University of Exeter Medical School
Dr Simon Satchell, University of Bristol
Dr Mick Craig, University of Exeter Medical School

Project Details:
One in three people will develop hypertension, which can result in fatal organ damage, e.g. stroke, heart and renal failure. One billion hypertensives worldwide have been diagnosed and 1.5 billion are predicted by 2025. In 95% of all hypertensive patients the cause is unknown. Remarkably, despite the availability of a range of pharmacological agents, clinicians are unable to restore blood pressure to normal levels in approximately 14% of patients with hypertension.

In recent years the connection between the kidneys and brain in cardiovascular disease has gained increasing interest. This is based upon clinical and epidemiological observations that kidney failure is associated with high sympathetic drive and incidence of failure of other organs. Indeed, recent clinical trials have shown that both blood pressure and sympathetic nerve activity are reduced after bilateral renal nerve denervation in some drug-resistant hypertensive patients. Mechanistically, most clinicians assume this denervation isolates the kidney from sympathetic drive, but recent evidence suggests this to be an oversimplification. Indeed, research suggests that afferent input from diseased kidneys to the CNS may play a key role in regulating sympathetic activity, and hence blood pressure; this underscores the need for more detailed translational research.

The overall aim of this project is to compare peripheral and central control over sympathetic tone. The specific aims are:
1. Determine which spinal and supraspinal neurons afferent input from the kidneys to CNS.
2. Determine the role of modulating efferent sympathetic drive from spinal/ supraspinal segments on renal nerve activity and blood pressure.
3. Attempt to manipulate spinal relay neuronal activity to control blood pressure in vivo, in healthy and hypertensive rodents.

Aim 1 and 2 will be approached using optogenetic-assisted circuit-mapping methods, using retrograde and anterograde viral vectors to label populations of neurons that project both from the renal nerve to dorsal spinal cord, and from ventral spinal cord to the kidney, plus determine which higher CNS regions control this circuit. Combined with immunohistochemical methods, this will allow us to identify specific markers for spinal neruons (e.g. neurotensin, parvalbumin) that are involved in this circuit. Aim 3 will build upon this knowledge, and use chemogenetic inhibition and excitation of these spinal neurons, or ‘up-stream’ neurons in higher CNS, in an attempt to modulate sympathetic activity, and thus control blood pressure.

This project will use advanced methods in mapping and manipulating neuronal circuitry in healthy rodents and in established models of hypertension. As such, this presents the student with an exceptional opportunity to be trained in both ex vivo and in vivo methodology that spans peripheral and central neurophysiology within an exciting new era of biomedical research addressing blood pressure control.

To apply for the project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.