The Role Of Huntingtin Misfolding And Oligomerization In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$474,329.00
Summary
Mutations in the huntingtin gene cause Huntington's disease by making the gene product aggregate together into non-normal and different sized polymers. However, it is not understood how this process causes cells to die, largely because we don't understand how the abnormal forms accumulate in cells over time. We will examine where in cells the abnormal shapes accumulate and how they cause toxicity. This research will identify critically-needed therapeutic targets against Huntington's disease.
The Influence Of Gamma-secretase Complex Subunits On The Production Of Alzheimer Amyloid Peptides
Funder
National Health and Medical Research Council
Funding Amount
$641,540.00
Summary
Alzheimer's disease is a devastating illness of the aged population and represents a major socio-economic problem in Australia. There is no cure or effective treatment for the illness. A toxic protein fragment known as Abeta amyloid accumulates in the brain of the diseased patients. This is produced by an enzyme called gamma-secretase. This project will investigate different forms of gamma-secretase to gain information useful for developing Alzheimer-specific drugs with little side-effects.
Structure-function Inter-relationships Of Small Heat-shock Chaperone Proteins
Funder
National Health and Medical Research Council
Funding Amount
$240,990.00
Summary
In vivo, most proteins only function over a narrow temperature or pH range. For example, if the solution containing a particular protein is heated (stressed), the protein will unfold, aggregate and potentially precipitate. The act of protein precipitation is an irreversible process that, in many cases, has deleterious consequences for cell viability. Protein precipitation is associated with a diversity of diseases, e.g. cataract and neurodegenerative diseases such as Alzheimer's, Creutzfeldt-Jak ....In vivo, most proteins only function over a narrow temperature or pH range. For example, if the solution containing a particular protein is heated (stressed), the protein will unfold, aggregate and potentially precipitate. The act of protein precipitation is an irreversible process that, in many cases, has deleterious consequences for cell viability. Protein precipitation is associated with a diversity of diseases, e.g. cataract and neurodegenerative diseases such as Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases. Nature has evolved cellular mechanisms to minimise protein misfolding, aggregation and precipitation which principally utilise a diverse group of controlling or regulatory proteins called molecular chaperones. Amongst the most important of these are the small heat-shock proteins (sHsps) which are found in all organisms. sHsps function by interacting in a very efficient manner with destabilised proteins to prevent their precipitation. Little is known, however, about the structure of sHsps nor the mechanism by which they perform their chaperone action. This proposal will address these fundamental aspects via the use of a variety of spectroscopic techniques, principally nuclear magnetic resonance (NMR) spectroscopy.Read moreRead less
Structure And Function Of The AMPK Glycogen-binding Domain
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results i ....The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. I have previously found that AMPK localizes to a source of cellular energy called glycogen (sugar stores) via one part that I have called the glycogen-binding domain. In this application I aim to obtain a thorough understanding of the molecular basis of how the glycogen-binding domain affects AMPK function in muscle and heart following exercise. In addition this research may lead to the identification of new molecules, similar to glycogen, that are important for AMPK regulation and may lead to the development of a new class of drugs for Type 2 Diabetes. Research into AMPK promises to dramatically increase our knowledge of how to reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an understanding of the reasons these diseases develop.Read moreRead less
TRF2 Protein And T-loop Replication In Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
Telomere loss acts as a clock telling cells when to stop proliferating. Cancer cells ignore this clock and grow indefinitely by preventing the normal loss of telomeres. Little is known about one of the methods cancers use to preserve telomeres, called ALT, which is employed by some brain tumours and other cancers. We will determine if the TRF2 protein is involved in controlling ALT. This will lay the basis for future anti-cancer treatments targeted at ALT.
Function Of Factor H-related Protein-5, A Novel Human Plasma Complement Protein Found In Glomerular Immune Deposits
Funder
National Health and Medical Research Council
Funding Amount
$186,430.00
Summary
The Investigators have recently discovered a new protein which is present in human blood and is also seen in the diseased kidneys of patients with nephritis. The new protein is present in all types of nephritis that are caused by antibodies together with another part of the immune system, called the complement system, which is know to have an important role in causing tissue damage in immune diseases. The new protein is a part of the complement system but its exact function is not yet known. The ....The Investigators have recently discovered a new protein which is present in human blood and is also seen in the diseased kidneys of patients with nephritis. The new protein is present in all types of nephritis that are caused by antibodies together with another part of the immune system, called the complement system, which is know to have an important role in causing tissue damage in immune diseases. The new protein is a part of the complement system but its exact function is not yet known. The protein is likely to be important in immune diseases because it is so commonly found in diseased kidneys and other organs with complement-associated disease. In this project we will conduct a series of experiments which will determine how the new protein works in the complement system and also how important the protein is in causing kidney damage in nephritis. Nephritis is the commonest cause of kidney failure in Australia and research directed towards the mechanism of kidney damage has the potential to produce new types of therapy. The complement system also has a major role in other inflammatory diseases and in body defense systems (such as protection against microbial attack). The complement system must be able to distinguish between foreign particles and the body's own tissue and this new protein may have a role in the appropriate regulation of complement to attack the right things in the body. Elucidation of the function of this protein may well assist, therefore, in developing therapies for a variety of inflammatory diseases and infectious diseases, in addition to nephritis.Read moreRead less
DNA-binding proteins regulate gene expression and co-ordinate normal patterns of development. We are investigating a set of DNA-binding proteins, termed the Ikaros family. These proteins are known to be important regulators of white blood cell production and mutations that interfere with Ikaros activity are associated with aggressive childhood leukaemias that are resistant to treatment. Recently, it has become apparent that Ikaros proteins also regulate genes in red blood cells. One observation ....DNA-binding proteins regulate gene expression and co-ordinate normal patterns of development. We are investigating a set of DNA-binding proteins, termed the Ikaros family. These proteins are known to be important regulators of white blood cell production and mutations that interfere with Ikaros activity are associated with aggressive childhood leukaemias that are resistant to treatment. Recently, it has become apparent that Ikaros proteins also regulate genes in red blood cells. One observation is that Ikaros plays a role in silencing the foetal haemoglobin genes. The haemoglobin genes have been extensively studied because diseases, such as beta-thalassaemia, which are caused by mutations in the adult haemoglobin genes, are among the most common genetic diseases known. One strategy to alleviate beta-thalassaemia centres around re-activating the foetal globin genes and thereby re-supplying globin to adults who have only mutant forms. In this context, the observation that Ikaros plays a role in foetal globin silencing is of considerable medical significance. We have recently identified two new regulatory proteins that are related to Ikaros and are found in red blood cells. Little is known about these proteins but they can directly bind to Ikaros and they are capable of silencing gene expression. We therefore wish to test the hypothesis that they work together with Ikaros to silence gene expression. Ultimately we expect that understanding how these proteins and Ikaros operate will suggest new strategies for re-activating the silent foetal globin genes to treat beta-thalassaemia, as well as preventing the proliferation of white blood cells carrying mutant Ikaros proteins.Read moreRead less
Discriminating The Roles Of Inhibin A And B In Reproductive Systems
Funder
National Health and Medical Research Council
Funding Amount
$312,576.00
Summary
Inhibin A and B are essential for the regulation of fertility based on their dual inhibitory actions on follicle stimulating hormone secretion by the pituitary and egg and sperm production in the gonads. An understanding of the mechanisms involved in inhibin A and B actions will: (1) identify novel biomarkers for the diagnosis of reproductive disorders (2) enhance the management of reproductive disorders (3) identify targets for the development of therapeutic means of modulating fertility