Pathophysiological characterization of novel biomarkers and development of tests for diagnosis and monitoring osteoarthritis

Osteoarthritis (OA) is one of the most common chronic diseases affecting the adult population. Currently, definitive diagnosis of OA is usually made using plain x-rays at relatively advanced stages of the disease when there is irreparable damage to the joint(s). We have demonstrated that serum levels of macromolecules (biomarkers) can provide a way of identifying patients with early OA and those likely to progress (Sharif et al, 1995 & 2004, Davies et al 2007). However, currently available biomarkers lack specificity and sensitivity to pick up individual patient from control or identify a patient who will progress over time. Therefore there is an urgent need to seek novel and more specific-biomarkers for investigation of OA and other joint diseases. The discovery of OA-specific biomarkers offers the potential for early diagnosis and therefore more effective management of the condition. Our recent proteomic studies (de Seny et al 2011) have identified 4 novel biomarkers for OA, 3 of which have been identified by mass spectrometry as V65 Vitronectin, complement C3f and connective tissue-activating peptide III (CTAPIII). The aim of the proposed study is to carry out biochemical characterization of V65 and C3f, determine their physiological functions and develop new assays for quantitative measure of these two novel biomarkers in patients.

Our laboratory is in the Faculty of Health Sciences at the University of Bristol, and the PhD student will work as part of a team involved in application of biomarkers to explore the mechanisms of development and progression of knee OA. The PhD student will carry out in vitro pathophysiological characterization of the biomarkers using joint tissues from OA patients and determine their potential role in joint destruction in OA. You will develop novel biomarker assays using panels of monoclonal and polyclonal antibodies already available in our laboratory, and carry our validation of these assays using serum samples from patients and controls. The project will also involve the use of monoclonal and polyclonal antibodies for immuno-localization of these peptides (biomarkers) in joint tissues, and relate these measurements to concentrations of the biomarkers in blood, key x-ray and MRI features of the disease. We have a steady supply of OA and control cartilage from total joint replacement surgery (from the Avon Orthopaedic Centre) and cadavers (from Anatomy dissection room) which would be used for histological analyses/grading of the OA cartilage and related to measurements of the novel biomarkers in blood from these subjects. The project will also benefit from our on-going collaboration with the National Institute of Health in USA, as serum samples and patients’ clinical data may be available from the NIH osteoarthritis biomarker initiative for final validation of the assays.

The PhD candidate should have basic knowledge/experience of tissue culture, enzyme-linked immunosorbent assays (ELISA), handling clinical and imaging data (x-ray and MRI) from large numbers of patients and able to apply appropriate statistical tests to analyse the data.

Research facility and training opportunity
The PhD student will be based in the new, purpose built laboratories in the School of Clinical Sciences at the Faculty of Health Sciences, University of Bristol, and would be a member of the Musculoskeletal Research Unit (MRU). The MRU is led by world-class researchers in Rheumatology and it has a strong emphasis on translational research. During the first term the student will attend various induction courses and lectures. Throughout the studentship you would be encouraged to attend weekly seminars at the MRU given by world-class scientists in the field of Rheumatology and particularly osteoarthritis research. You will also attend weekly lab meetings and would be encouraged to discuss your laboratory work at these meetings. You will gain experience in writing manuscripts for publication and presenting at conferences from your supervisor(s) and from various short courses organized and run by the university. There is support available from post-doctoral scientists in our group and from experienced laboratory technicians and managers in the department to become proficient in all the laboratory techniques required for this project.