Signaling Pathways To Enhance Potency Of AMPK-targeting Drugs
Funder
National Health and Medical Research Council
Funding Amount
$661,966.00
Summary
Sedentary lifestyles and consumption of high energy foods has led to epidemics of obesity-related metabolic diseases that place enormous financial and medical burden on the Australian economy. An attractive drug target to treat these diseases is AMP-activated protein kinase (AMPK) which functions as both a cellular fuel gauge and co-ordinator of whole-body metabolism. Our goal is to improve AMPK drug potency by identifying novel processes that sensitize AMPK to drugs.
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560987
Funder
Australian Research Council
Funding Amount
$156,697.00
Summary
Robust High Resolution Gene and Protein Expression Analysis Facilities in WA. Biological research is playing an increasingly important role in keeping agriculture internationally competitive and helping to unravel the basic mechanisms underpinning plant and animal health. This collaborative research equipment will greatly enhance and extend our existing functional genomic facilities in WA, allowing robust pre-fractionation of samples for directed proteomic analysis within complex systems and al ....Robust High Resolution Gene and Protein Expression Analysis Facilities in WA. Biological research is playing an increasingly important role in keeping agriculture internationally competitive and helping to unravel the basic mechanisms underpinning plant and animal health. This collaborative research equipment will greatly enhance and extend our existing functional genomic facilities in WA, allowing robust pre-fractionation of samples for directed proteomic analysis within complex systems and allowing accurate and sensitive measurement of gene expression. Both of these are critical for analysis of low abundance components involved in signalling and regulatory functions in biological samples.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453722
Funder
Australian Research Council
Funding Amount
$385,240.00
Summary
Collaborative Genomics, Proteomics and Metabolomics Facility for Western Australia. Plant and animal agriculture in Western Australia contributes $6billion per annum to the nation. Biotechnology is playing an increasingly important role in keeping agriculture internationally competitive, and requires investment in platform technologies to underpin basic and applied research. This collaborative project will provide state-of-the-art equipment and extend existing joint facilities that will enable ....Collaborative Genomics, Proteomics and Metabolomics Facility for Western Australia. Plant and animal agriculture in Western Australia contributes $6billion per annum to the nation. Biotechnology is playing an increasingly important role in keeping agriculture internationally competitive, and requires investment in platform technologies to underpin basic and applied research. This collaborative project will provide state-of-the-art equipment and extend existing joint facilities that will enable WA researchers to carry out high quality research on genomics, proteomics and the metabolic functioning of plants and animals. This will generate new knowledge, provide advanced training and help ensure that Australian R&D in agricultural biotechnology stays at the forefront and benefits the nation.Read moreRead less
Targeted Development Of AMPK Β2-isoform Allosteric Activators
Funder
National Health and Medical Research Council
Funding Amount
$898,147.00
Summary
Sedentary lifestyles and consumption of high energy foods has led to dramatic increases in the incidence of diseases associated with metabolic dysregulation e.g. type 2 diabetes. An attractive drug target to treat these diseases is AMP-activated protein kinase (AMPK) which functions as a cellular fuel gauge. We have discovered a new drug that crucially activates the form of AMPK found in metabolically active organs. We aim to develop this drug to unlock new therapeutic opportunity.
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
Metabolic Stress Sensing By AMPK: Implications For Energy Balance And Isoform-targetting Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$632,188.00
Summary
Metabolic diseases such as obesity, type 2 diabetes and cardiovascular disease impose enormous medical and economic burdens on Western societies. Our research is focussed on the enzyme AMP-activated protein kinase (AMPK) which acts as the fuel gauge of the cell and is a promising drug target for combating metabolic diseases. Our discoveries provide critical insight on how AMPK is switched on by both energy demand and drugs, and will greatly assist development of AMPK-targetted therapeutics.
Genome Approaches to Investigate Metabolic Coordination in Plant Cells. Metabolism of C and N in legume nodules requires interaction between the symbiotic bacteria and plant organelles, particularly metabolism in plastids and mitochondria. Fixed N is assimilated through the de novo synthesis of purines in both plastids and mitochondria. However, each of the nine pathway enzymes is encoded by a single gene, indicating each protein is targeted to both organelles. Purine metabolism will provide ....Genome Approaches to Investigate Metabolic Coordination in Plant Cells. Metabolism of C and N in legume nodules requires interaction between the symbiotic bacteria and plant organelles, particularly metabolism in plastids and mitochondria. Fixed N is assimilated through the de novo synthesis of purines in both plastids and mitochondria. However, each of the nine pathway enzymes is encoded by a single gene, indicating each protein is targeted to both organelles. Purine metabolism will provide a model to assess the more general occurrence of dual-targeted proteins in plants. The aim is to identify and eventually exploit the signalling mechanism(s) that mediate communication between plastids and mitochondria.Read moreRead less
Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by ....Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by FOXO proteins. Although very basic in nature, these projects will identify how FOXO proteins regulate muscle cell building and wasting and, therefore, present a potential therapeutic target for muscle wasting diseases, making this project highly significant.Read moreRead less
The function of the ribbon structure of the Golgi apparatus in vertebrates. The aim of the project is to determine the function of the Golgi ribbon structure in higher order cell functions, including metabolism, cell cycle, and cell polarity in both cultured cells and whole organisms. Understanding of the functions of the Golgi has been restricted to the regulation of glycosylation and membrane transport. However, it is now recognised that the Golgi apparatus feeds into the wiring of a range of ....The function of the ribbon structure of the Golgi apparatus in vertebrates. The aim of the project is to determine the function of the Golgi ribbon structure in higher order cell functions, including metabolism, cell cycle, and cell polarity in both cultured cells and whole organisms. Understanding of the functions of the Golgi has been restricted to the regulation of glycosylation and membrane transport. However, it is now recognised that the Golgi apparatus feeds into the wiring of a range of cellular networks in higher organisms such as cell polarisation, directed migration, metabolism and autophagy. Vertebrates have evolved mechanisms for joining individual Golgi stacks into a ribbon structure. The relevance of this ribbon structure remains a mystery. The project aims to answer this major question in cell biology.Read moreRead less