Identifying The Targets Of Myeloperoxidase-derived Oxidants In Plasma And Cells
Funder
National Health and Medical Research Council
Funding Amount
$237,258.00
Summary
Myeloperoxidase (MPO) is a haem enzyme, released by activated white blood cells, that catalyses the production of highly damaging chlorinated oxidants. These oxidants are known to play a major role in the human immune system by killing bacteria and other invading pathogens. However, excessive or misplaced generation of these oxidants results in tissue damage. This damage has been implicated in development of disease. For example, there is strong evidence for the involvement of MPO, and the oxida ....Myeloperoxidase (MPO) is a haem enzyme, released by activated white blood cells, that catalyses the production of highly damaging chlorinated oxidants. These oxidants are known to play a major role in the human immune system by killing bacteria and other invading pathogens. However, excessive or misplaced generation of these oxidants results in tissue damage. This damage has been implicated in development of disease. For example, there is strong evidence for the involvement of MPO, and the oxidants that it produces, in atherosclerosis. This disease is responsible for the death of around 40 % of the Australian population. There is no doubt that the oxidants produced by MPO cause major damage to tissues and extensive cell death. However, the mechanisms involved in this process remain to be established, due to a lack of sensitive and specific techniques for examining oxidant-mediated damage to individual target molecules. This study will identify the key targets of MPO-derived oxidants in plasma and cells using novel labelling techniques. This will provide valuable information about the mechanisms of oxidative damage and cytotoxicity. This will be important in the design of potential therapeutic agents to modulate and prevent the progression of degenerative diseases, such as atherosclerosis, that are linked with MPO.Read moreRead less
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