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The role of TRPM8 in human inflammatory bowel disease


   Barts and The London School of Medicine and Dentistry

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  Dr D Bulmer, Prof A Blackshaw  No more applications being accepted  Funded PhD Project (European/UK Students Only)

About the Project

MRC PhD Studentship
Centre for Digestive Diseases
Blizard Institute
Barts and the London School of Medicine & Dentistry
Queen Mary University of London

Applications are invited from graduates with a BSc (First or Upper Second) or MSc (Distinction or Merit). Previous research experience would be an advantage. This 3 year studentship will commence on 1st October 2014 and the applicant will be based in the School's Whitechapel Campus. This is an exciting opportunity for a graduate from disciplines related to Immunology, Neuroscience or Nutrition

Background:
Mint has been used as a treatment of skin and bowel disorders for centuries. This natural remedy approach has been medicinalised with the advent of licensed, delayed release formulation of peppermint oil, such as COLPERMIN® or MINTEC® and these treatments have been shown to reduce spasm during colonoscopy (5) and symptom scores in patients with irritable bowel syndrome (IBS) (3). The discovery that the transient receptor potential ion channel melastatin 8 (TRPM8) is the receptor for the biological effects of mint has opened up a gold rush of TRPM8 drug discovery in which the efficacy of these natural treatments can be greatly improved by generation of synthetic compounds with superior bioavailability, potency and selectivity (1). Our work has shown recently that TRPM8 is located on pain sensing nerves innervating the bowel,. Activation of TRPM8 causes an acute activation of sensory nerves which is followed by a persistent desensitization, and so overall TRPM8 acts to “switch off” pain sensing nerves (2).
We found recently that TRPM8 expressing nerves terminate in close apposition to dendritic cells in mouse colonic mucosa (paper in preparation), and this neuroimmune interaction grows markedly in experimental colitis. Deletion of TRPM8 in these sensory nerves worsened experimental colitis, and application of the TRPM8 agonist icilin alleviates colitis suggesting that TRPM8 plays a protective role during inflammation (4). However, strikingly in humans, our preliminary data indicate TRPM8 is found mainly on immune cells in the bowel. These are not CD3 cells, so a major aim is to determine which subtype they are and how TRPM8 affects their function. There is indirect evidence that TRPM8 is found on macrophage-like cell lines (6), but this is so far all the information in the literature. Another striking feature of our data is that it appears so far like TRPM8 cells are only found in the gut mucosa of IBS and inflammatory bowel disease (IBD) patients, not in controls. This fits with a protective role in gut mucosa.
There are potent agonists for TRPM8, like WS-12, that are safe for human use. There are delivery systems that allow release of drugs at high concentrations specifically in the colon, but no-one has combined the two. This is our ultimate aim after we find out how TRPM8 works.
Plan: 1. Sensory nerve recordings in mouse colon. The student will determine the mechanism and kinetics of TRPM8 activation and desensitization in this preparation (2), and how does cross-desensitization occur. Noxious chemical, inflammatory, persistent and transient mechanical deformation will all be tested.
2. Cytokine release from human colonic mucosal biopsies will be measured by our multiplex (MAGPIX) assay, and will determine how cytokine release profiles are affected by TRPM8 activation in IBS and IBD (Th1, 2, 17). This will be done in unstimulated and IL-1β activated specimens.
3. Double-label immunohistochemistry will determine which populations of cells express TRPM8, using characteristic human markers (e.g. CD3, 33, 68, 119), and peptide expression (e.g. β-endorphin, proteases).
4. Fluorescence-Activated Cell Sorting will determine which populations of circulating human immune cells express TRPM8, and therefore their likely fate in the gut.
The project will involve collaborations with other groups in the Blizard Institute and continued work with Prof Raz.

Informal Enquiries can be made to: Dr D Bulmer e-mail: [Email Address Removed]

Funding Notes

This Studentship is funded by the MRC and comes with a tax-free stipend of approximately £15,726 per annum. It is open to UK Nationals, EEA/Swiss migrant workers and non-UK nationals with indefinite leave to remain in the UK who will have three years ordinary residence in the UK prior to the start of the studentship. University tuition fees (at UK/EU levels) will be met by the funding body.
Please refer to website for full eligibility details:
http://www.mrc.ac.uk/Fundingopportunities/Applicanthandbook/Studentships/Eligibility/index.html

References

To apply, please send a copy of your CV and a covering letter to the supervisor

Closing date: 11th November 2013

Interviews will be held on 6th December 2013.

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