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Novel anti-inflammatory mechanisms of cyclic-AMP in vascular smooth muscle cells

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

About This PhD Project

Project Description

A self-funded PhD studentship is available at the University of Bristol to study novel anti-inflammatory mechanisms of cyclic-AMP in vascular disease.

Cardiovascular diseases represent a major cause of mortality and morbidity across the Western world. Chronic inflammation is a critical hallmark in the development of multiple occlusive vascular diseases including transplant vasculopathy, interventional restenosis and atherosclerosis. Vascular smooth muscle cells (VSMCs) resident in the vessel wall undergo a unique, coordinated morphological and functional transition between contractile and synthetic states in response to vascular injury and disease. Inflammatory activation of medial VSMCs results in secretion of a diverse range of pro-inflammatory mediators such as cytokines, chemokines and adhesion molecules, in response to a variety of signals in the surrounding environment. VSMC inflammatory activation contributes to vessel pathophysiology, vascular disease progression and ultimately, adverse clinical outcome. Therefore, it is of considerable therapeutic importance to identify novel mechanisms that regulate the VSMC inflammatory response.

It has been known for several decades that 3’5’-cyclic adenosine monophosphate (cAMP), a prototypical second messenger, transducing the action of a variety of G-protein-coupled receptor ligands, has potent immunosuppressive and anti-inflammatory actions. These actions have been attributed in part to the ability of cAMP-induced signals to interfere with the function of the proinflammatory transcription factor Nuclear Factor-kappaB (NF-κB). However, the mechanisms underlying the modulation of NF-kB activity by cAMP remain unclear.

Our group had characterised the anti-mitogenic properties of cAMP in vascular cells. We demonstrated that elevated levels of cAMP disrupts the polymerisation of the actin cytoskeleton in these cells. This in turn inhibits the activity of a transcriptional co-factor called MKL1, which is required for expression of genes needed for cell proliferation. Our recent data indicates that MKL1 may also act as a co-factor for NF-kB and hence promote expression of NF-kB dependent pro-inflammatory genes. We propose to test the following hypothesis:

The anti-inflammatory properties of cAMP in VSMC are due to disruption of the cytoskeleton and subsequent repression of MKL1-NF-kB dependent pro-inflammatory gene expression.

In this project, you use a variety of molecular and cell biology techniques to test this hypothesis. These will include, primary cell culture, RNA manipulations, qPCR, gene transfer, siRNA gene silencing, luciferase reporter gene assays and western blotting.

This three year PhD studentship will characterise theses novel molecular mechanisms using a range of molecular and cell biology techniques, including primary cell culture, RNA manipulations, qPCR, gene transfer, siRNA gene silencing, luciferase reporter gene assays and western blotting. The project offers the opportunity to study in an excellent research environment, in a research institute with world class facilities and resources devoted to understanding the cellular and molecular mechanisms of cardiovascular disease and driving new translational therapies for patients. We have an opportunity available for exceptional candidates with an interest in the areas of vascular biology, cell signalling and gene expression regulation and drug-discovery. Candidates should have at least a 2:1 BSc in a biological science.

Tuition fees: Standard University of Bristol tuition fees plus £10,000/year bench fees.

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