Offres & annonces

PhD Studentship: Exploring the metabolome of the ageing and degenerating musculoskeletal in the genetic disease Alkapton

23/07/2015
  • £14,057 pa Stipend
  • Institute of Ageing and Chronic Disease, Department of Musculoskeletal Biology
  • Location: University Campus
  • Ref: PHD-GALLAGHER/WWW
  • Closing date for receipt of applications: Fri, 24 Jul 2015 17:00:00 BST

This is a collaborative project between the University of Liverpool, The Royal Liverpool University Hospital and Agilent Technologies. Alkaptonuria (AKU) is a rare genetic disease resulting from a single gene defect in tyrosine metabolism leading to an elevation in circulating homogentisic acid (HGA). Over time HGA polymerizes, termed ochronosis, depositing in joint tissue leading to accelerated ageing and early onset, severe osteoarthropathy. The rapid and predictable progress of joint degeneration makes AKU an ideal model system for investigating ageing and destruction of joints.  Our studies on tissue samples from AKU patients and AKU mice have revealed a spectrum of previously unrecognised microanatomical, cellular and biochemical changes in joints which have subsequently been detected also in human osteoarthritis (OA). These include early changes in the integrity of collagen fibrils, the role of calcified cartilage in the initiation of OA, thinning and cracking of the subchondral plate with subsequent formation of high density mineralised protrusions, and aberrant bone remodelling. All of these are easily recognisable in the severe phenotype of AKU but require more careful observation in OA because they occur at a lower frequency. We have also undertaken 2 pilot studies with Agilent Technologies, in human and in mouse, which revealed that in AKU the upstream and downstream tyrosine pathway is disrupted as expected, but in addition there are changes in the cartilage and bone metabolomes which can be dissociated from the tyrosine metabolome.

In the proposed project, we will examine the serum and urine metabolomes by targeted and non-targeted metabolomics in two cohorts of AKU patients by semi-quantitative high resolution mass spectrometry (using 6560 LC-TOF-MS) and quantitative targeted liquid-chromatography tandem mass spectrometry (LC-MS/MS). Multivariate analysis will be undertaken using Mass Profiler Professional, (Agilent) to identify and correlate age, disease and therapy-related effects. The software allows principal component and clustering analysis. Agilent Pathway Architect will be used to mine metabolomics data and understand the differences in the context of biological pathways.

The student will undertake all standard training associated with membership of the Institute of Ageing and Chronic Disease, including regular attendance at Institute seminars. In addition they will attend the bimonthly meeting of the RLUH/UoL AKU research group, at which they will be expected to present at least 3 times per year. The student will benefit from practical training in experimental techniques both in the laboratories of the Bone and Joint Research Group and in the Department of Clinical Chemistry. They will be given training on state of the art LC-TOF-MS and LC-MS/MS instruments from Agilent both within the department and also on special Agilent training courses. They will also be trained in the use of Agilent analytical software, Mass Profiler Professional and Agilent Pathway Architect. The student will be encouraged to attend PhD training courses run by the Bone Research Society and the European Calcified Tissues Society.

The Institute of Ageing and Chronic Disease and its constituent departments are fully committed to promoting gender equality in all activities. In recruiting researchers and academic staff we stress the supportive nature of the working environment and the flexible family support that the University provides. The Institute has recently been awarded a Silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

References:
  • Helliwell TR, Gallagher JA, Ranganath LR. Alkaptonuria--a review of surgical and autopsy pathology. Histopathology. 2008 53:503-12.
  • Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, Gallagher JA. The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis Rheum. 2011 63:3887-96.
  • Preston AJ, Keenan CM, Sutherland H, Wilson PJ, Wlodarski B, Taylor AM, Williams DP, Ranganath LR, Gallagher JA, Jarvis JC. Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis. 2014 73:284-9.
  • Genovese F, Siebuhr AS, Musa K, Gallagher JA, Milan AM, Karsdal MA, Rovensky J, Bay-Jensen AC, Ranganath LR. Investigating the Robustness and Diagnostic Potential of Extracellular Matrix Remodelling Biomarkers in Alkaptonuria. JIMD Rep. 2015 Mar 19. [Epub ahead of print]
  • Hughes AT, Milan AM, Davison AS, Christensen P, Ross G, Gallagher JA, Dutton JJ, Ranganath LR. Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry. Ann Clin Biochem. 2015 Jan 27. [Epub ahead of print]
  • Ranganath LR, et al Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily
  • nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis. 2014 Dec 4. [Epub ahead of print]

 

We are seeking applications from candidates with a first or upper second class honours degree in a relevant subject, including graduates in biological or biochemical sciences with an interest in bioinformatics or graduates in chemistry with an interest in applying their skills in biomedical research.  Applications including CV and the names of two referees should be addressed by email to Prof Jim Gallagher (jag1@liv.ac.uk) with copy to iacdpgr@liv.ac.uk by 17th July 2015.

Liste de diffusion du RFMF ouverte à tous et gratuite.

Depuis le 1er Janvier 2017 la liste de diffusion est ouverte à tous, Pour vous inscrire suivez le lien.

Réseau Francophone de Métabolomique et Fluxomique
TOP