The Role Of Clusterin In Preventing Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$352,662.00
Summary
In atherosclerosis, plaques are formed when damaged low density lipoprotein (LDL) and fibrinogen are deposited inside blood vessels. Clusterin is a protein that stabilises damaged clients in soluble complexes, thus preventing their deposition. This project will investigate the ability of clusterin to prevent the deposition of damaged LDL and fibrinogen. Elucidation of mechanisms for preventing protein deposition will identify novel therapeutic targets for the treatment of atherosclerosis.
Counteracting Age-associated Neurodegenerative Diseases Using Chaperone-based Amyloid Disaggregases
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
In neurodegenerative diseases such as Alzheimer’s disease, proteins form clumps through changes in structure due to mutations or proteotoxic chemical insults. The formation of these toxic clumps causes brain cells to die prematurely triggering symptoms such as dementia. I have identified a molecular machine in human cells that efficiently clears these clumps. We are now developing strategies to activate this machine to repair damaged brain cells to slow/reserve neurodegenerative diseases.
The Effect Of Hypochlorite On The Toxicity And Clearance Of The Alzheimer’s Disease-associated Amyloid Beta Peptide
Funder
National Health and Medical Research Council
Funding Amount
$461,496.00
Summary
Alzheimer’s disease (AD) is the leading cause of dementia worldwide and a growing burden on our aging society. Recent studies support the idea that in AD a deleterious relationship exists between inflammation in the brain and the accumulation of amyloid beta (A?), a peptide with toxic properties. This proposal aims to examine the details of this relationship with a focus on the toxicity and clearance of A? when it is modified by hypochlortie, a chemical that is generated during inflammation.
PROTEIN TARGETS FOR THE STEROID RECEPTOR MODULATOR, CYCLOPHILIN 40
Funder
National Health and Medical Research Council
Funding Amount
$374,828.00
Summary
Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immun ....Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immunophilins as cyclophilin 40 ( CyP40), a protein that binds the immunosupressant drug, cyclosporin A. We have recently found that, in addition to binding to hsp90, CyP40 may bind to and regulate the function of other proteins which are important in how cells grow and die. The aims of this project are to study how CyP40 binds to hsp90 and to these other proteins and to determine the functional outcomes of these interactions.Read moreRead less
The Role Of Molecular Chaperones And Proteases In Mitochondrial Function
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Mitochondria are essential organelles providing the cell with essential molecules and being the source of oxidative energy in the cell. They are at the centre of many clinical conditions, ranging from genetic to common neurological diseases and other conditions related to ageing. We have been defining the way in which mammalian cells respond to the accumulation of unfolded proteins within the mitochondrial compartment and have found this produces what we have called the Mitochondrial Stress Resp ....Mitochondria are essential organelles providing the cell with essential molecules and being the source of oxidative energy in the cell. They are at the centre of many clinical conditions, ranging from genetic to common neurological diseases and other conditions related to ageing. We have been defining the way in which mammalian cells respond to the accumulation of unfolded proteins within the mitochondrial compartment and have found this produces what we have called the Mitochondrial Stress Response, a process that results in the selective upregulation of a suite of genes encoding mitochondrial stress proteins. This application deals with the question of the consequences to the cell of the creation of proteolytic environment. We have found that the two major proteases of the mitochondrion are upregulated and that this results in a marked increase in the rate of degradation of mitochondrial proteins. We aim to determine the specific roles of individual proteases in this process and the consequences of this proteolysis on the efflux of peptides from the mitochondria. This question has important medical implications, as one of the consequences of defects in mitochondrial function is the loss of cells from the affected tissue. We will also address the question of how mitochondrial biogenesis is regulated. We have recently found that the cytosolic molecular chaperone Hsp90 is required for protein import into mitochondria in mammalian cells. Since Hsp90 has hitherto been shown to be a key regulatory component in the steroid hormone and tyrosine kinase signalling pathways, this finding raises the possibility that protein import and thereby mitochondrial biogenesis may be regulated via the involvement of Hsp90.Read moreRead less