About the Project
Arthritis is a leading cause of disability in the western world and its total (direct and indirect) costs have been estimated to be over £30 billion annually in the UK. Osteoarthritis is the most common arthritis affecting over 8 million people in the UK. It causes progressive breakdown of articular cartilage and bone, leading to joint failure and need for prosthetic joint replacement. Rheumatoid arthritis is the most common chronic inflammatory disease affecting over 400,000 people in the UK. It causes joint damage and devastating deformities.
A hallmark of joint pathology is synovitis, a chronic inflammation of the membrane lining the joint cavity called synovium, which leads to tissue outgrowth, causing joint pain and damage. The key cell sustaining synovial outgrowth via proliferation is the synovial fibroblast. Data in our lab indicate that synovial fibroblasts are a subset of the endogenous pool of mesenchymal stromal/stem cells (MSCs) in synovium, suggesting the intriguing possibility that the synovial outgrowth in arthritis results from an abnormal/dysfunctional MSC that, via interactions with surrounding cells, undergoes uncontrolled expansion. We postulate the macrophage to be a key extrinsic modulator of MSC function in synovium because of the vicinity of macrophage-like synoviocytes to MSCs, the central role of macrophages in arthritis pathogenesis, and their known role in regulating stem cell functions in other tissues.
We thus hypothesise that the interplay in the synovial lining between MSCs and the adjacent macrophages results in uncontrolled proliferation of MSCs to sustain synovial outgrowth, leading to chronicity of arthritis and progression of damage.
The objectives of this PhD project will be:
(1) To co-detect macrophages and MSCs in histological sections from mouse models of arthritis, available in our lab, and characterise anatomical location and phenotype of MSCs and macrophages (M1 vs. M2).
(2) To validate transgenic mice allowing monitoring of genetically labelled macrophages and MSCs in synovium during arthritis.
(3) To establish and validate in vitro co-culture systems of MSCs and macrophages. We will use mouse MSCs and macrophages isolated from the transgenic reporter mice via cell sorting. Human cells will also be used in parallel for clinical relevance.
(4) To investigate the molecular interplay modulating MSC and macrophage function in vitro. The effects of macrophages onto MSC phenotype and function (migration and invasion, proliferation and differentiation) will be studied.
(5) A selected molecular target will be tested as proof-of-concept therapeutic approach to arthritis using standard mouse models of rheumatoid-like inflammatory arthritis or osteoarthritis. Mice will be monitored longitudinally via clinical scoring and in vivo imaging, and killed for histological analysis. Synovial MSC proliferation and joint pathology including damage will be studied and compared with control animals.
The student will employ a wide range of techniques. These will include in vivo experimentation including transgenic mice, mouse models of arthritis and in vivo imaging; histological sample preparation and analysis, immunohistochemical and immunofluorescence stainings, and light and confocal laser scanning microscopy. The student will further perform FACS and cell sorting, cell culture, proliferation, differentiation, migration and invasion assays.
Day-to-day research training will be provided by members of the Arthritis & Regenerative Medicine Laboratory. Cell culture training will be provided by the technicians of the Tissue Culture Facility, and microscopy training through attendance of the yearly microscopy course run by the Microscopy Core Facility. Finally, the student will also be encouraged to complete a ScotPIL course and apply for a Personal Licence.
This PhD programme will be undertaken in the Arthritis & Regenerative Medicine Laboratory (http://www.abdn.ac.uk/acamh/research/arthritis/index.php) in the Institute of Medical Sciences (http://www.abdn.ac.uk/ims). The lab is part of the Aberdeen Centre for Arthritis & Musculoskeletal Health (http://www.abdn.ac.uk/acamh) and a partner of the Arthritis Research UK Tissue Engineering Centre, which is led by the University of Cambridge and based at five sites:
- the University of Aberdeen;
- the University of Cambridge;
- the University of Newcastle;
- the University of Keele/the Robert Jones & Agnes Hunt Hospital NHS Foundation Trust in Oswestry; and
- the University of York.
In addition to the training courses provided by the University of Aberdeen Graduate School, the Arthritis & Regenerative Medicine lab holds regular lab meetings and journal clubs in which the PhD student will actively take part to enhance his/her academic skills.
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