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Investigation of mechanistic links between metabolic stress, inflammation, and apoptosis in osteoarthritis


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Project details
Osteoarthritis (OA) is the most common joint disease in the elderly population and is the forth leading cause of disability in the world. Current treatment for osteoarthritis is largely limited to pain relief and improvement of functional status as there are no pharmacological agents capable of retarding the progression of OA or preventing OA. The aetiology of OA is complex and diverse, involving a range of biomechanical, biochemical and genetic factors which converge on a final common pathway characterised by a progressive focal loss of articular cartilage, bone remodeling and variable synovial inflammation. Unraveling the mechanisms of cartilage destruction in OA is the main focus of our current research. Our previous studies have shown that cell death by apoptosis (programmed cell death) is up-regulated in OA cartilage and that cyclic mechanical loading, a known risk factor for development of OA, can increase chondrocyte death by apoptosis (Clements et al 2001). We have also shown that chondrocyte apoptosis is on average 3 times higher in OA cartilage compared to normal (Sharif et al 2004), and that the rate of apoptosis increases rapidly during progression of cartilage damage (Zamli et al 2014). More recent data from other groups suggest that chondrocyte respond to mechanical stress by expressing various mediators of inflammation and apoptosis, and that synovial inflammation is associated with severe pain and rate of cartilage damage in OA. The aim of this PhD project is to test the hypothesis that these processes (metabolic stress, inflammation, chondrocyte apoptosis and cartilage damage) are intrinsically linked, and understanding the sequence and relationship between these processes and their pharmacological control will help to unravel the precise role of these processes and lead to identification of novel therapeutic targets for this very common condition.

The project will involve application of a wide range of biochemical and molecular biology techniques including, gel electrophoresis, western blotting and immuno-histochemistry to look at expressions of various mediators (both mRNA and protein) of the above processes in human articular cartilage. We have a steady supply of OA and control cartilage from elective total joint replacement surgery (from the Avon Orthopaedic Centre) and cadavers (from Anatomy dissection room) which would be used for tissue culture and immuno-histochemical analyses. The PhD candidate should have basic knowledge and some experience of simple biochemical and/or molecular biology techniques, and able to apply appropriate statistical tests for analysis of the data.

Research facility and training opportunity
The PhD student will be based in the new, purpose-built laboratories in the Faculty of Health Sciences at the University of Bristol and would be a member of the Musculoskeletal Research Unit (MRU). 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 groups and from experienced laboratory technicians and managers in the school to become proficient in all the laboratory techniques required for this project. The purpose built, research facility at the School of Clinical Sciences has 20 post-doctoral scientists and 10 full-time PhD students and provide an ideal environment for intellectual development and translational research.

References

Clements KM, Bee ZC, Crossingham GV, Adams MA, Sharif M. How severe must repetitive loading be to kill chondrocytes in articular cartilage? Osteoarthritis Cartilage. 2001;9:499-507.

Sharif M, Whitehouse A, Sharman P, Perry M, Adams M. Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and to expression of caspase-3. Arthritis and Rheumatism 2004;50: 507-515.

Zamli Z, Adams MA, Tarlton JF and Sharif M. Increased Chondrocyte Apoptosis Is Associated with Progression of Osteoarthritis in Spontaneous Guinea Pig Models of the Disease. Int. J. Mol. Sci. 2013, 14(9), 17729-17743.

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