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Inhibition of phosphodiesterase-4B as therapeutic strategy for cognitive impairment

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  • Full or part time
    Dr S Clapcote
    Dr J. Johnston
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Expressions of interest are invited from individuals with at least a 2:1 degree in a relevant subject who are interested in working in the labs of Dr Steve Clapcote and Dr Jamie Johnston on a research project investigating inhibition of phosphodiesterase-4B (PDE4B) as a therapeutic intervention for cognitive impairment.

PDE4B is one of four enzymes (PDE4A-D) that selectively hydrolyse cAMP. Rolipram, which inhibits all PDE4 subtypes, has shown a variety of therapeutic effects in cognitively-impaired laboratory rodents. However, the drug causes nausea and emesis in humans, owing to PDE4D-specific effects, thus limiting its use for therapeutic purposes. To develop a treatment for cognitive impairment that has the potential benefits of rolipram, but without the nausea, we are focussing on specific inhibition of PDE4B. To this end, we generated PDE4B-Y358C mice that have a catalytic mutant form of PDE4B with a 27% decreased ability to hydrolyse cAMP. We recently reported (McGirr et al., 2016) that young adult PDE4B-Y358C mice show enhanced learning and memory; enhanced long-term potentiation and less synaptic depression in hippocampal slices; increased dendritic spine density in the hippocampus and amygdala; and enhanced neurogenesis in the adult dentate gyrus.

You, the PhD student, will use a broad range of specialised methods to investigate the effects of genetic and pharmacological inhibition of PDE4B in aged (18-month-old) mice that are usually affected by age-related cognitive decline. The project may later be extended to include a mouse model of Alzheimer’s disease. The results of the research will be critical in deciding whether inhibition of PDE4B is a strategy worth pursuing as a therapeutic intervention for cognitive impairment.

You will receive training in cutting edge methods and approaches (electrophysiology, imaging, transgenic models, behavioural approaches etc.); you will also receive training in transferable skills (project design and management, presentations, problem-solving etc.) which you will be able to apply in your future career. The supervisors will encourage interaction with other research groups via journal clubs, seminars involving external speakers and attendance at conferences.

Funding Notes

Individuals interested in pursuing this PhD project, and who hold or expect to gain at least a 2:1 degree in a relevant subject, should e-mail a CV and cover letter explaining their motivation to Dr Steve Clapcote ([Email Address Removed]) by the deadline of midnight on 20th May 2018. A suitable candidate will be identified by interview (which can be via telephone or Skype) and encouraged to apply online at https://leeds.onlinesurveys.ac.uk/centrally-funded-research-postgraduate-scholarships-2018 for the Emma and Leslie Reid Scholarship before the deadline of 5pm on 1st June 2018. The successful applicant will work on a project currently funded by Research Councils UK.

References

McGirr A, Lipina TV, Mun HS, Georgiou J, Al-Amri AH, Ng E, Zhai D, Elliott C, Cameron RT, Mullins JG, Liu F, Baillie GS, Clapcote SJ, Roder JC. Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition. Neuropsychopharmacology. 2016 Mar;41(4):1080-92. doi: 10.1038/npp.2015.240.

Titus DJ, Wilson NM, Freund JE, Carballosa MM, Sikah KE, Furones C, Dietrich WD, Gurney ME, Atkins CM. Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor. J Neurosci. 2016 Jul 6;36(27):7095-108. doi: 10.1523/JNEUROSCI.3212-15.2016.

How good is research at University of Leeds in Psychology, Psychiatry and Neuroscience?

FTE Category A staff submitted: 44.05

Research output data provided by the Research Excellence Framework (REF)

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