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Novel EPAC1 inhibitors to enhance insulin sensitivity in vascular endothelial cells

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  • Full or part time
    Dr S Yarwood
    Dr G Barker
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Reference number: FS/17/12/32703
Funder: British Heart Foundation
Web-links: http://www.yarwoodlab.hw.ac.uk/
https://www.hw.ac.uk/schools/engineering-physical-sciences/staff-directory/stephen-yarwood.htm

Eligibility requirements: Requirements are a first or upper second class chemistry or relevent biological sciences degree (eg biochemistry, biotechnology, pharmacology etc). The application should include an up-to-date CV and letters of reference from two academic referees.

Contact for enquiries: [email protected]

Likely interview period: May to June

PhD start Date: 1st October 2017

Description of Project: Cardiovascular diseases (CVDs), like atherosclerosis, are the leading cause of disability and death in patients with metabolic syndrome (met-syn) and Type 2 Diabetes (T2D). CVDs are associated with altered functioning of “vascular endothelial cells” (VECs) that line large and small blood vessels. If unchecked, defective VEC function can lead to heart disease, stroke and amputation. The narrowing of the arteries responsible for heart disease and stroke is triggered by chemicals in the blood called "cytokines" which trigger inflammatory signals that turn-on genes responsible for defective VEC function, including the inhibition of insulin's protective actions in these cells. EPAC1 is a key enzyme that regulates the natural defences in VECs thereby blocking the processes that lead to damaging inflammation. We now aim to find out how exactly how EPAC1 controls these events as well as the important actions of insulin that are normally blocked by inflammation in T2D and met-syn.

The intracellular target of EPAC1 is the human SOCS3 gene, which is a negative regulator of insulin production, insulin receptor activation and vascular inflammation and is therefore a valid therapeutic target for the treatment of CVDs associated with met-syn. We are therefore developing novel inhibitors of EPAC1 activity that may enhance beneficial insulin signalling in VECs. We will use biophysical analysis to determine the mechanisms of action of EPAC1 inhibitors and then apply them to determine the molecular basis linking EPAC1 activation to the transcriptional induction of the SOCS3 gene and regulation of insulin and inflammatory signalling in VECs. This will include the evaluation of the roles of key transcription factors and the importance of tethering EPAC1 to the nuclear pore complex, using super-resolution microscopy techniques. We will also determine the role of the EPAC1/SOCS3 signalling axis in the control of insulin signalling towards nitric oxide production in VECs. These objectives will define a central role for EPAC1/SOCS3 signalling in the control of the cardiovascular complications of met-syn and lead to new therapeutic intervention strategies.

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