Oxidation Of Arterial Extracellular Matrix By Myeloperoxidase-derived Oxidants
Funder
National Health and Medical Research Council
Funding Amount
$183,266.00
Summary
It is well established that changes occur in the composition and nature of the extracellular matrix present in the artery wall during the development of atherosclerosis. The changes that occur in this matrix affect both the mechanical and physical properties of the arterial wall (e.g. its ability to cope with the high pressures genrated by the pumping of blood from the heart) and the adhesion of cells. It is well established that certain key cell types do not adhere well, or grow properly, on al ....It is well established that changes occur in the composition and nature of the extracellular matrix present in the artery wall during the development of atherosclerosis. The changes that occur in this matrix affect both the mechanical and physical properties of the arterial wall (e.g. its ability to cope with the high pressures genrated by the pumping of blood from the heart) and the adhesion of cells. It is well established that certain key cell types do not adhere well, or grow properly, on altered or damaged matrix and this can result in either the loss of key cell types from the artery wall (e.g. loss of endothelial cells) and - or the proliferation and invasion of cells from other sources (e.g. smooth muscle cell invasion into the intimal space). There is circumstantial evidence that some of these changes occur via the formation of oxidants by the heme enzyme myeloperoxidase which is released from activated white cells. In this study we will employ recently developed analytical techniques to examine the nature of the alterations that are present in atherosclerotic plaques in comparison to normal human artery samples, and investigate the mechanisms by which such alterations arise. We will seek evidence for, or against, the involvement of myeloperoxidase-derived oxidants in the observed changes using specific markers which we have developed for the presence of such damage. This information will allow the rational design of strategies to interfere with the progression of atherosclerosis, which is the major killer of Australians.Read moreRead less
Defective Cell Migration As A Mechanism Of Dysregulated Asthmatic Airway Repair
Funder
National Health and Medical Research Council
Funding Amount
$616,712.00
Summary
Injury of the airway epithelium (cells lining the airways) is normally repaired by a process involving the deposition of specific proteins by the airway epithelial cells, promoting them to attach and migrate to cover the injury. These cells appear to be abnormal in asthmatics, in that they fail to repair. By studying specimens from healthy, allergic and asthmatic children we will determine the factors that influence the ability of these cells to repond to an injury in a normal manner specificall ....Injury of the airway epithelium (cells lining the airways) is normally repaired by a process involving the deposition of specific proteins by the airway epithelial cells, promoting them to attach and migrate to cover the injury. These cells appear to be abnormal in asthmatics, in that they fail to repair. By studying specimens from healthy, allergic and asthmatic children we will determine the factors that influence the ability of these cells to repond to an injury in a normal manner specifically through their ability to migrate.Read moreRead less
I am a basic scientist with an interest in the cellular biology of the ovary, and the roles of the matrix between cells of the ovary in controlling fertility and hormone synthesis.
High-affinity Protease-resistant Analog Of Insulin-like Growth Factor Binding Protein-2: Potential Cancer Co-Therapeutic
Funder
National Health and Medical Research Council
Funding Amount
$294,423.00
Summary
In many human cancers, including prostate and breast cancer, serum levels of insulin-like growth factor (IGF)-II are elevated, and this growth factor has been strongly implicated in promoting the progression of these tumours. The action of IGF-II in stimulating tumour growth is mediated through Type 1 IGF receptors on the surface of the cells. The IGF binding protein, IGFBP-2, has been shown to increase the action of IGF-II in some cancer cells in vitro. by binding to the outside of the cells as ....In many human cancers, including prostate and breast cancer, serum levels of insulin-like growth factor (IGF)-II are elevated, and this growth factor has been strongly implicated in promoting the progression of these tumours. The action of IGF-II in stimulating tumour growth is mediated through Type 1 IGF receptors on the surface of the cells. The IGF binding protein, IGFBP-2, has been shown to increase the action of IGF-II in some cancer cells in vitro. by binding to the outside of the cells as an IGF-II-IGFBP-2 complex and then presenting the IGF-II to the receptor by a process of sustained release. We propose to produce a very high affinity form of insulin-like growth factor binding protein-2 (OOptimised IGFBP-2O) which will sequester the IGF-II and effectively prevent it from binding to the receptor or the native IGFBP-2. We shall also engineer the OOptimised IGFBP-2O so that it is unable to bind to the outside of the cells. With this novel peptide, OOptimised IGFBP-2O, we will test the hypothesis that the growth of insulin-like growth factor (IGF)-dependent tumours can be arrested by preventing the localisation and presentation of IGF-II to IGF receptors. We expect that the availability of such a sequestering agent for IGF-II will increase the effectiveness of current cancer chemotherapy agents since it is known that IGF-II can help save cancer cells from chemotherapy-induced death.Read moreRead less
Bridging The Gap Between Cartilage Biology And Osteoarthritis Risk Prediction
Funder
National Health and Medical Research Council
Funding Amount
$512,256.00
Summary
Osteoarthritis is a painful and debilitating cartilage disease affecting just under 1 in 10 Australians and costs the Australian economy roughly $12 billion per year. This project will develop computational models of cartilage with the ability to incorporate genetic and environmental risk factors into a predictive model of cartilage disease.
The Role Of Force-sensing Ion Channels In Melanoma Migration
Funder
National Health and Medical Research Council
Funding Amount
$553,848.00
Summary
Metastasis of melanoma cells away from the primary tumour site carries a very poor patient prognosis.This research aims to characterise a novel signalling pathway that can regulate the migration (movement) of melanoma cells. This signalling pathway depends on force-sensing platforms that can rapidly convert physical inputs from the environment into an electrical signal within the cell. We are working to understand how these force-sensors function.