For further details relating to any of the projects below please contact the director
Project 1. A new wound healing agent
Synopsis: The healing of wounds is a complex process involving a number of stages, including coagulation, inflammation, remodeling and finally development of full strength skin. Impaired wound healing and/or skin ulcers occur in patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure sores and burns. Despite intense investigation, the precise mechanisms associated with impaired healing are poorly understood. APC is a serine protease that plays a central role in physiological anticoagulation. APC potently activates gelatinase A, an enzyme that plays a prominent role during the remodeling phase of wound healing and angiogenesis. Our preliminary experiments provide very strong evidence that APC accelerates wound healing using both cultured cells and a rat skin wounding model. This work extends beyond cutaneous ulcers. It has application to the healing of other tissues such as cartilage and bone that have been damaged by either disease, such as arthritis, or injury. We have Honours, Masters and PhD projects available which will examine the laboratory or clinical aspects of this project.
Project 2. The role of activated protein C in the arthritic joint
Synopsis: Activated protein C (APC) is a naturally occurring protein found in the blood and thought to be responsible for preventing excess clotting. We have recently shown that APC can enhance the activity of gelatinase A and contribute to healing. This project will examine whether APC is elevated in the joints of patients with RA and whether APC modulates joint pathology in RA. This work should improve our understanding of the role of APC in RA and may ultimately lead to a new therapeutic approach to arthritis. A Masters or PhD project is available for this project.
Project 3. Identification and prevention of gelatinase A activation pathways in rheumatoid arthritis (RA)
Synopsis: The infiltration of new blood vessels (angiogenesis) is important in
the development of a number of diseases, including joint destruction in the
synovium of patients with arthritis. An essential step of angiogenesis is the
secretion of a matrix-degrading enzyme, gelatinase A, by the cells that line
the blood vessels (endothelial cells). Gelatinase A is secreted as an inactive
enzyme and must be activated. We are examining the pathways involved in its
activation using joint tissue derived from RA patients. In addition, selective
inhibitors of these pathways are being tested in vitro for their potential to
prevent excessive gelatinase A activation. This study
aims to elucidate potential novel therapies for RA. This project would suit a
Synopsis: In the normal hand there is a thin lining of tissue called tenosynovium, which surrounds the tendons, but in rheumatoid arthritis, this tenosynovium proliferates and becomes destructive. In 50% of these patients the tenosynovium actually invades the tendon itself, which in the long term may lead to tendon rupture with consequent joint disability. It is in the hand that these changes have the greatest impact, with the patient losing the ability to perform even the simplest tasks of daily living. Despite this common condition, little research has been done looking at the factors that allow tenosynovium to become "invasive." We are investigating the mechanisms involved in tenosynovial invasion of tendons. In contrast to joint disease, current medical treatment for rheumatoid arthritis does not appear to be effective for tendon disease and an improved understanding of the latter will allow the development of better therapies, perhaps avoiding the need for repeated surgery. Aspects of this work would contribute towards an Honours, Masters of PhD project.
Synopsis: Two characteristic features of RA are the presence of areas of focal bone erosions at the margins of affected joints, for example the metacarpophalangeal joint, and the formation of invasive pannus tissue beneath the synovial membrane. The proposed project will examine the breakdown of extracellular matrix, and more specifically, will address the mechanisms of bone erosion in arthritis. The involvement of MMPs in bone erosion in RA will be studied. The matrix metalloproteinases (MMPs) are thought to play an important role in the pathogenesis of RA. MMPs-1, -2, -3 and -9 are elevated in RA patients, and MMPs-1, -2 and -9 have been linked to the formation of bone erosions in RA. Most studies examining MMPs and bone erosions have not differentiated between erosive and non-erosive synovium from within the same joint. One hypothesis of this project is that synovium produces differing levels of MMPs depending on its location within the joint. This project would suit a PhD candidate.