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EASTBIO: AMPK-dependent regulation of neuronal excitability, breathing and oxygen supply


Project Description

Deanery of Biomedical Sciences
Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. It is generally accepted that a fall in arterial oxygen increases afferent discharge from the carotid bodies to the brainstem and thus delivers increased ventilatory drive, which restores oxygen supply and protects against hypoventilation and apnoea. However, the precise molecular mechanisms involved remain unclear. We recently identified as critical to this process the AMP-activated protein kinase (AMPK), which is key to the cell-autonomous regulation of metabolic homoeostasis. This observation is significant for many reasons, not least because recent studies suggest that the gene encoding the AMPK-α1 catalytic subunit has been subjected to natural selection in high-altitude populations. It would appear, therefore, that evolutionary pressures have led to AMPK being utilized to regulate oxygen delivery and thus energy supply to the body in the short, medium and longer term. Contrary to current consensus, however, our findings suggest that AMPK regulates ventilation at the level of the caudal brainstem, even when afferent input responses from the carotid body are normal. We therefore hypothesized that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. More significantly still, AMPK deficiency led to marked hypoventilation, rather than hyperventilation, and frequent prolonged apneas during hypoxia. Therefore, further investigations will not only extend our understanding of the hypoxia-responsive neural networks that regulate breathing and oxygen supply, but reveal as yet undiscovered, brainstem nuclei that are critical to this process, where AMPK deficiency and consequent dysfunction may precipitate sleep-disordered breathing and hypertension associated with either ascent to altitude or metabolic syndrome-related disorders. The present project will utilize confocal imaging and electrophysiology, to explore further the neuronal mechanisms and brainstem circuits through which AMPK deficiency precipitates respiratory dysfunction.
References
Evans AM, Mahmoud AD, Moral-Sanz J, Hartmann S. (2016). The emerging role of AMPK in the regulation of breathing and oxygen supply. Biochem J, 473, 2561–2572.
Mahmoud, A.D., Lewis, S., Juricic, L., Udoh, U.A., Hartmann, S., Jansen, M.A., Ogunbayo, O.A., Puggioni, P., Holmes, A.P., Kumar, P., Navarro-Dorado, J., Foretz, M., Viollet, B., Dutia, M.B., Marshall, I., Evans, A.M. (2016). AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea. AJRCCM, 193, 1032-1043.
Ikematsu, N., Dallas, M. L., Ross, F.A., Lewis, R.W., Rafferty, J.N., David, J.A., Suman, R., Peers, C., Hardie, D.G., Evans, A.M. (2011). Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. PNAS, 108, 18132-18137.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body. EU applicants without a history of residency in the UK are eligible to apply, but would only be awarded the fees (not the stipend). All candidates should have or expect to have a minimum of an upper 2nd class degree in an appropriate discipline.

References

Download application and reference forms via: http://www.eastscotbiodtp.ac.uk/how-apply-0
Completed application form along with your supporting documents should be sent to our PGR student team at [email protected] by 5th January 2020.

References: Please send the reference request form to two referees. Completed references for this project should also be returned to [email protected] by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.

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