Exploring the gene regulation networks governing mitochondrial biogenesis in Arabidopsis. Mitochondria, subcellular organelles that perform many functions indispensable to plant growth and productivity, are dynamic compartments whose protein complement changes dramatically during plant development and under stress. Yet, the cellular processes that regulate the production of these organelles are virtually unknown. By combining conventional approaches with an extremely powerful holistic method for ....Exploring the gene regulation networks governing mitochondrial biogenesis in Arabidopsis. Mitochondria, subcellular organelles that perform many functions indispensable to plant growth and productivity, are dynamic compartments whose protein complement changes dramatically during plant development and under stress. Yet, the cellular processes that regulate the production of these organelles are virtually unknown. By combining conventional approaches with an extremely powerful holistic method for simultaneously examining the expression patterns of every gene in the model plant Arabidopsis, this project will identify proteins that regulate mitochondrial biosynthesis and uncover the gene networks that these proteins control. The project outcomes will provide new opportunities for the rational manipulation of plant growth and productivity.Read moreRead less
Function And Pathophysiological Role Of A Novel Glucose Transporter Expressed In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$216,412.00
Summary
Diabetes is a disorder of metabolism resulting from a combination of deficiency of insulin and defective action of the insulin that is present. The most prominent metabolic abnormality is high blood glucose, which is often not satisfactorily corrected by insulin treatment. One of the main reasons for the high blood glucose is reduced uptake of glucose by muscle tissue. The mechanism by which insulin enhances glucose entry into muscle cells involves mobilisation of a specific protein from the glu ....Diabetes is a disorder of metabolism resulting from a combination of deficiency of insulin and defective action of the insulin that is present. The most prominent metabolic abnormality is high blood glucose, which is often not satisfactorily corrected by insulin treatment. One of the main reasons for the high blood glucose is reduced uptake of glucose by muscle tissue. The mechanism by which insulin enhances glucose entry into muscle cells involves mobilisation of a specific protein from the glucose transporter protein family, which has been designated GLUT4. Surprisingly, animals that have been genetically altered to eliminate orknockout GLUT4 production do not develop diabetes. This finding has led to the theory that there is a backup glucose transporter protein that can prevent diabetes when there is a problem with GLUT4 function. We have recently discovered a new member of the glucose transporter protein family that could potentially function as either a parallel or a backup system for GLUT4. This new glucose transporter, which we have called GLUT8, is present in human muscle tissue and studies in other cells have shown that it alters its distribution within the cell in reponse to insulin. We now want to study in more detail the role of this new glucose transporter in muscle tissue and how it functions compared with GLUT4. In particular, we think it is possible that Type 2 diabetes occurs when there is not only a problem with the mobilisation of GLUT4 but also a defect in the production or function of GLUT8. If this is the case, then increasing GLUT8 production might improve glucose transport into muscle tissue and so improve control of blood glucose levels in diabetes.Read moreRead less
Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investiga ....Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investigation of this protein presents an opportunity for the investigator to work at the forefront in this field adding to Australia's scientific leadership in the area. It also represents an ideal project for post-graduate training and is a collaboration between groups in Brisbane and Melbourne. Read moreRead less
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
Transcription-based Identification Of Insulin Resistance Subtypes
Funder
National Health and Medical Research Council
Funding Amount
$341,883.00
Summary
A key feature of type 2 diabetes is the failure of metabolic tissues such as muscle and fat to respond to normal levels of insulin. This 'insulin resistance' is caused by a number of mechanisms. We will use cutting-edge technology to identify small sets of genes that define each variety of insulin resistance. These gene sets will be used to diagnose sub-types of insulin resistance and will facilitate the development of personalised therapies to effectively treat individuals with type 2 diabetes.
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.
Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a fra ....Integration of Cellular Gene Regulation Processes. This research program aims to identify specific transcriptional regulatory networks in yeast, to determine how some of these networks interact with each other and within these networks to identify the roles of genes whose functions are currently unknown. It will identify systems regulating genes concerned with one-carbon metabolism, cellular responses to oxidative stress and developmental changes associated with meiosis. It will provide a framework to test regulatory network models and to analyse the molecular basis of interactions between control systems. This research will eventually provide the ability to predict how cells respond to drugs and other environmental stimuli.Read moreRead less