Assembly And Misassembly Of Mitochondrial Respiratory Chain Complex I
Funder
National Health and Medical Research Council
Funding Amount
$520,520.00
Summary
Mitochondria are the powerhouses in our cells. They burn the carbon fuels we eat and store the energy by making ATP that is used for functions such as muscle contraction and triggering of nerves. Mitochondrial Complex I is a molecular motor that helps to make ATP. “Mitochondrial disease” is often seen when Complex I is not built properly and this results in early childhood death. In this project we will study how Complex I is built and how the mitochondria responds to assembly problems.
Characterising An Important Control Point In Cholesterol Synthesis Beyond HMG-CoA Reductase
Funder
National Health and Medical Research Council
Funding Amount
$480,739.00
Summary
The statins are the ‘go-to’ drugs for treating heart disease; blocking a very early, highly-controlled step in the pathway producing cholesterol. However, they inhibit the production of other vital molecules which explains why some patients do not tolerate them. We have identified that a later enzyme in this pathway is also highly controlled and here aim to characterise the molecular mechanisms involved. This work could translate into the development of even safer drugs for treating cholesterol- ....The statins are the ‘go-to’ drugs for treating heart disease; blocking a very early, highly-controlled step in the pathway producing cholesterol. However, they inhibit the production of other vital molecules which explains why some patients do not tolerate them. We have identified that a later enzyme in this pathway is also highly controlled and here aim to characterise the molecular mechanisms involved. This work could translate into the development of even safer drugs for treating cholesterol-related diseases.Read moreRead less
Mechanisms Of Oxidised Protein Accumulation In Ageing Cells
Funder
National Health and Medical Research Council
Funding Amount
$429,000.00
Summary
Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down ....Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down by the cells and replaced, but in many age-related diseases this process fails. The most common source of protein damage is attack by oxygen-derived free radicals. These are by-products of our body's need for oxygen and can originate from atmospheric pollutants. Oxygen rusts metal, makes fat go rancid and can cause irreparable damage to proteins and other biological molecules. Free radical damage contributes to the development of many age-related diseases such as atherosclerosis and neurodegenerative diseases such as Alzheimer's disease. The accumulation of damaged proteins can cause cell death. Our knowledge of the mechanisms by which cells remove proteins damaged by oxygen and the reasons for their accumulation is limited. In this project we will use a novel technique we have developed to generate oxidised proteins in ageing cells. We will identify cellular mechanisms required for the efficient removal of damaged proteins and those mechanisms which fail in ageing cells. We will focus on a group of proteins which protect damaged proteins from aggregating and accumulating and we will examine how we can prevent the accumulation of oxidised proteins by stimulating the body s defence mechanisms. Since the population of Australia is ageing, diseases of ageing are going to consume an increasing amount of the national health budget. A better knowledge of these cellular mechanisms will allow us to design effective prevention and treatment strategies which are at present lacking.Read moreRead less
Regulation Of Protein Kinases And Their Substrates
Funder
National Health and Medical Research Council
Funding Amount
$553,197.00
Summary
Our research is concerned with the control of the body's energy metabolism via an enzyme called AMPK. This enzyme is at the hub of metabolic control in response to diet and exercise. AMPK controls energy expenditure in response to demand as well as appetite. It is well recognized that diet and sedentary life-styles are major contributors to obesity and cardiovascular disease. We are testing how a new drug activates AMPKand how energy expenditure can be increased.
The Role Of Protein Kinase C Epsilon In The Generation Of Lipid-Induced Insulin Resistance In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Insulin normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized by a failure of these tissues to respond adequately to insulin. This loss of sensitivity to the hormone is known as insulin resistance, and has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. Certain fat molecules are able to cause the activation of pathways within cells which can in ....Insulin normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized by a failure of these tissues to respond adequately to insulin. This loss of sensitivity to the hormone is known as insulin resistance, and has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. Certain fat molecules are able to cause the activation of pathways within cells which can interfere with the normal signalling of insulin. We have recently found that mice lacking an enzyme thought to be involved in such negative pathways are less susceptible to insulin resistance caused by high-fat feeding. The aim of this project is to investigate the mechanism by which this enzyme contributes to inhibition of insulin action. We will determine the step in normal insulin signalling which is blocked by the activation of the enzyme upon increased fat supply. This will help us to determine the pathway leading from the enzyme to insulin signalling. We will also identify the particular form of fat which leads to activation of the enzyme. This work will lead to a better understanding of the mechanisms by which fats can play a role in the generation of insulin resistance, so that they can be targeted both for the development of new and more effective treatments for the disorder and for prevention of its onset.Read moreRead less
Signal transduction and the control of bacterial respiration by the NtrYX two component regulatory system. This proposal will define the structural and functional properties of the NtrYX two component signal transduction and define its role in the regulation of respiratory gene expression. The human pathogen Neisseria gonorrhoeae will be used as a model organism for a diverse range of 'oxidase positive' bacteria that possess NtrYX. The outcome will be a major contribution to the understanding of ....Signal transduction and the control of bacterial respiration by the NtrYX two component regulatory system. This proposal will define the structural and functional properties of the NtrYX two component signal transduction and define its role in the regulation of respiratory gene expression. The human pathogen Neisseria gonorrhoeae will be used as a model organism for a diverse range of 'oxidase positive' bacteria that possess NtrYX. The outcome will be a major contribution to the understanding of way in which respiratory gene expression is controlled in bacterial species for which Escherichia coli is not a suitable model. Read moreRead less
Viewing The Cellular Responses In Huntington’s Disease Through An Aggreomics Framework
Funder
National Health and Medical Research Council
Funding Amount
$363,218.00
Summary
Huntington disease results from a mutation that causes the Htt protein to form abnormal toxic clusters in neurons that eventually leads to cell death. This project will develop and apply new technology to identify how the clustering process damages cells and will measure all the gene expression changes that occur during the clustering process. The project offers much potential for revealing new therapeutic targets to this incurable disease.
AMPK Control Of Lipid Metabolism: Role In Regulating Energy Balance And Insulin Sensitivity
Funder
National Health and Medical Research Council
Funding Amount
$614,437.00
Summary
The control of appetite and maintenance of a lean body mass along with exercise is important for protecting the body against obesity and increased incidence of Type 2 diabetes and cardiovascular disease. We are investigating how the regulation of lipid metabolism controls appetite and body weight and the extent to which these same controls are important for drugs acting to lower blood lipid levels.
In Vivo And Biochemical Appraisal Of Mitochondrial STAT3
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
The Signal Transducer and activator of transcription 3 (STAT3) protein is over-expressed or activated in most cancers. The paradigm for STAT3's role in cancer is that it drives the expression of genes which support tumour growth. Recently I found that STAT3 controls the altered metabolic state required for cancer progression, both by control gene expression and by entering the mitochondria. I propose define the mechanism of STAT3 mitochondrial activity and then translate these findings into anim ....The Signal Transducer and activator of transcription 3 (STAT3) protein is over-expressed or activated in most cancers. The paradigm for STAT3's role in cancer is that it drives the expression of genes which support tumour growth. Recently I found that STAT3 controls the altered metabolic state required for cancer progression, both by control gene expression and by entering the mitochondria. I propose define the mechanism of STAT3 mitochondrial activity and then translate these findings into animal models of cancer.Read moreRead less
The selective elimination of mitochondria from yeast cells: regulation and molecular mechanism . For healthy cells the quality of the mitochondrion, the cellular power plant, must be maintained. The results of this research will contribute to an understanding of the molecular mechanism for the removal of mitochondria from the cell, and ultimately inspire strategies for the treatment of diseases that result from faulty mitochondria.