PhD Projects
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
PhD student.
Project 4. The
mechanism of tendon invasion by tenosynovium in rheumatoid arthritis
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.
Project 5. Mechanisms of bone erosion and matrix breakdown in arthritis.
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.
