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
The Complementary Effects Of Matrilins And WARP On Chondrogenesis Through TGF-beta Signaling
Funder
National Health and Medical Research Council
Funding Amount
$327,428.00
Summary
Osteoarthritis (OA), characterized by degeneration of articular cartilage matrix structure, is one of the most common types of arthritis. Although it is known that aging is a leading factor, the exact cause of degeneration of articular cartilage is not well understood. In order to aid the discovery of treatments and diagnostic tools for this joint disease, understanding functional and mechanistic properties of cartilage specific proteins, namely matrilins and WARP, is essential.
Molecular Mechanisms Of Disease In The Collagen VI-related Muscular Dystrophies
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
The inherited muscular dystrophies are an important cause of disability in Australia. This project concentrates on the second most common group of congenital muscular dystrophies - those caused by mutations in collagen VI and its interacting partners. We will determine how mutations affect the structure of the protein and how the muscle is disrupted by the mutations. This work will open the way for research into potential therapies. We will also find new genes that cause muscular dystrophy.
Pre-clinical Assessment Of Novel Growth Factor Complexes As A Topical Agent In The Treatment Of Deep
Funder
National Health and Medical Research Council
Funding Amount
$156,870.00
Summary
Healing of deep burns, unlike that of superficial injuries, often resolves with scarring. Scarring is reduced with rapid closure of burns. The CIs have discovered and patented novel growth factor complexes that stimulate the growth and migration of keratinocytes, cells derived from skin. Hence these complexes hold therapeutic potential for wounds that require rapid closure such as deep burns. This application will provide pre-clinical, proof-of-principle data to facilitate future patient trials.
The Role Of Tissue Factor In The Regulation Of Extracellular Matrix Remodelling And Angiogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal me ....The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal menstrual cycle, and for the normal growth and development of the placenta and a new baby. The processes by which these new blood vessels form and the factors contributing to the maintenance of their structure are incompletely understood. However, it is known that the interaction of cells and the surrounding extracellular matrix is critical for normal cell function and in particular for new blood vessel formation. Studies in this project will seek to define a relationship between some of the factors which regulate blood clotting, and those that regulate turnover of the extracellular matrix and new blood vessel formation. In particular, how blood clotting factors may be invovled in the regulation of the extracellular matrix will be studied in a rapidly developing tissue, the mouse placenta. The role of blood clotting factors in regulation of new blood vessel formation into an artificial avascular tissue will also be examined. These studies will employ some of the new genetic techniques to understand new roles for proteins which have been traditionally thought to act in only one way. This research has the potential to provide new insights into how blood vessels are formed and are subsequently maintained. This increased understanding will provide the knowledge required for the development of new therapeutic strategies to correct the process when it goes wrong, is unwanted or underdeveloped in human disease.Read moreRead less
Improving Muscular Dystrophy By Targeting The ADAMTS5 Metalloproteinase
Funder
National Health and Medical Research Council
Funding Amount
$658,571.00
Summary
Muscular dystrophy is a devastating childhood disorder. There is no cure and no effective therapy to stop the disease progressing to early death. Our pilot data show that muscular dystrophy in a mouse model is dramatically improved when the Adamts5 gene is inactivated. ADAMTS5 is an enzyme that remodels the extracellular matrix around cells. This suggests that inhibiting ADAMTS5 may be a new way to treat muscular dystrophy. We will test this idea in mice with muscular dystrophy
KIT As A Target For The Modification Of Vascular Proteoglycans And Prevention Of Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$342,864.00
Summary
Heart disease occurs when arteries supplying blood to the heart become blocked. One aspect of this blockage is the capture of fats from the blood, by artery wall structures called proteoglycans. Proteoglycans are made up of a core protein and sugar chains (GAGs). The stickier the GAGs, the more fats that are captured. No drug treatment acts directly on the artery wall to prevent heart disease. This project aims to identify steps that lead to stickier GAGs and therefore a potential drug target.