Understanding The Role And Mechanism Of Interaction Of Small Heat-shock Proteins In Age-related Disease
Funder
National Health and Medical Research Council
Funding Amount
$270,827.00
Summary
Protein precipitation is associated with a diversity of age-related diseases such as cataract and Alzheimer's. Within cells, a group of chaperones called the small heat-shock proteins (sHSPs) function by binding to destabilized proteins, however, common in vivo modifications can disrupt their cellular role leading to co-aggregation in a number of age-related diseases. This study will use state of the art mass spectrometry to examine the mechanism by which sHSPs interact with client proteins.
Investigating The Iron Proteome In Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$514,644.00
Summary
Iron is essential for brain function. When the delicate balance of metals in the brain is disturbed, neurodegenerative effects such as those seen in Alzheimer’s disease are observed. Although we know there is a link between iron and Alzheimer’s disease, we do not know which specific iron proteins are involved. This project will provide the first characterisation of different iron proteins in the brain to understand the mechanisms of disease and help in the search for new treatments.
Deciphering the cellular defences against aggregating proteins in human disease. Cells have inbuilt defences for coping with proteins that bend into abnormal sticky shapes that form toxic clusters. In many diseases, including Huntington's, the clusters severely damage nerve cells. This project will identify the genes and mechanisms cells use to protect themselves from toxic clusters, which could provide new therapeutic targets.
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989105
Funder
Australian Research Council
Funding Amount
$495,000.00
Summary
An Advanced Mass Spectrometry Facility for Applications in Proteomics and Organic Chemistry. Biomolecular research and research training, in which proteomics is core, has become a critical component of post-industrial development in the Hunter region. Development of a cutting edge proteomics facility will benefit a research community comprising over 50 researchers and 150 undergraduate students significantly enhancing their research productivity and translation of outcomes in areas of national i ....An Advanced Mass Spectrometry Facility for Applications in Proteomics and Organic Chemistry. Biomolecular research and research training, in which proteomics is core, has become a critical component of post-industrial development in the Hunter region. Development of a cutting edge proteomics facility will benefit a research community comprising over 50 researchers and 150 undergraduate students significantly enhancing their research productivity and translation of outcomes in areas of national importance. These include understanding the impact of the environment on plant and animal development, pest animal control, development of new biotechnology tools, new drugs and new methods for the detection of narcotics and explosives.Read moreRead less
Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs ....Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs) in insects, other mammalian IRPs probably also exist. These may be of equal importance in regulating apoptosis, especially in tissues where DIABLO is not expressed. The main aim of the proposed study is to idenitify and characterise other IRPs in mammalian cells.Read moreRead less
Function and modulation of the protein quality control network in mammalian mitochondria. This project has potential technological benefit in the areas of biotechnology and molecular medicine especially in relation to age-related cellular degeneration. As a result of our research outputs, strategies could be developed to either delay the onset or reduce the severity of diseases related to mitochondrial dysfunction. Training research scientists of the future, forms an integral part of our researc ....Function and modulation of the protein quality control network in mammalian mitochondria. This project has potential technological benefit in the areas of biotechnology and molecular medicine especially in relation to age-related cellular degeneration. As a result of our research outputs, strategies could be developed to either delay the onset or reduce the severity of diseases related to mitochondrial dysfunction. Training research scientists of the future, forms an integral part of our research program and our association with world leaders in the field provide excellent opportunity for exchange of personnel, ideas and emerging methodologies. This project will lead the way in this field and consequently will expand Australia's reputation at the forefront of scientific advancement. Read moreRead less
Imaging the action of antimicrobial peptides in living cells. The purpose of this project to use a special magnifying glass to watch molecules invading and killing cells. The outcome will be to identify the mechanism of cell killing to help in the future design of better antibiotics.
A proteomic approach to identifying the signaling pathway(s) by which acute oxidative stress causes cell death by apoptosis. Oxidative stress following traumatic injury (heart attack or stroke) is known to activate signaling pathways leading to programmed cell death (apoptosis). The aim of this project is to develop methods to identify the signaling proteins involved. Identifying proteins involved in causing cell death will be useful in developing diagnostic tools as well as providing potential ....A proteomic approach to identifying the signaling pathway(s) by which acute oxidative stress causes cell death by apoptosis. Oxidative stress following traumatic injury (heart attack or stroke) is known to activate signaling pathways leading to programmed cell death (apoptosis). The aim of this project is to develop methods to identify the signaling proteins involved. Identifying proteins involved in causing cell death will be useful in developing diagnostic tools as well as providing potential therapeutic possibilities.Read moreRead less