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
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
Structure and Function of the AMP-activated protein kinase. The AMP-activated protein kinase (AMPK) is a member of the metabolic stress sensing protein kinase subfamily that is present in all eukaryotes, including the yeast homologue, snf1p protein kinase essential for adapting to growth without glucose. The AMPK plays an important role in matching metabolism to nutrient supply and energy demand of perhaps all physiological processes. The aim of this project is to understand the structure and ....Structure and Function of the AMP-activated protein kinase. The AMP-activated protein kinase (AMPK) is a member of the metabolic stress sensing protein kinase subfamily that is present in all eukaryotes, including the yeast homologue, snf1p protein kinase essential for adapting to growth without glucose. The AMPK plays an important role in matching metabolism to nutrient supply and energy demand of perhaps all physiological processes. The aim of this project is to understand the structure and function of the AMPK. This work may provide important opportunities for drug design, understanding the impact of metabolism and ageing as well as increasing our knowledge of signalling pathways that control cellular events.Read moreRead less
Endosomal Protein Transport: From Molecular Structures to Biological Function. Intracellular transport of biomolecules through the endosomal organelle is critical for normal cellular processes such as signalling, homoeostasis and development. Defects in this fundamental process and subversion of it by bacterial and viral pathogens also lead to many different human diseases. This project will build on Australia's strong programme of structural and cellular biology research to develop key insights ....Endosomal Protein Transport: From Molecular Structures to Biological Function. Intracellular transport of biomolecules through the endosomal organelle is critical for normal cellular processes such as signalling, homoeostasis and development. Defects in this fundamental process and subversion of it by bacterial and viral pathogens also lead to many different human diseases. This project will build on Australia's strong programme of structural and cellular biology research to develop key insights into endosomal trafficking at the molecular level. Outcomes from this work will place Australia at the forefront of international efforts to understand this essential biological process and will have important implications for future design of pharmaceuticals.Read moreRead less
The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of ....The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of eEF2 in controlling protein synthesis, seek new substrates for eEF2 kinase and initiate work to elucidate the structure of this unusual enzyme. This will enhance, in a range of ways, fundamental understanding of cell physiology.Read moreRead less
Coordinating energy metabolism to enhance exercise capacity. Diet and exercise contribute to health and ageing productively whereas high caloric diets and sedentary life styles are deleterious. The enzyme AMPK regulates energy metabolism in response to diet and exercise and by studying it we expect to learn why diet and exercise are beneficial at the molecular level. This may allow the development of nutritional, exercise and drug strategies to enhance exercise capacity and well being during ....Coordinating energy metabolism to enhance exercise capacity. Diet and exercise contribute to health and ageing productively whereas high caloric diets and sedentary life styles are deleterious. The enzyme AMPK regulates energy metabolism in response to diet and exercise and by studying it we expect to learn why diet and exercise are beneficial at the molecular level. This may allow the development of nutritional, exercise and drug strategies to enhance exercise capacity and well being during ageing as well as suppress age onset diseases that include obesity diabetes cardiovascular disease hypertension and neurodegeneration.Read moreRead less
Systems therapeutics for metabolism: AMPK isoform specific drugs. Living cells have to maintain a steady balance between energy production and consumption in order to function properly. A key regulator of energy balance is an enzyme known as 5' AMP-activated protein kinase (AMPK), which regulates the burning and storage of fuels such as fat and sugars, in response to changes in energy demand. This project will provide a major advancement in our understanding of the regulation of AMPK at the mo ....Systems therapeutics for metabolism: AMPK isoform specific drugs. Living cells have to maintain a steady balance between energy production and consumption in order to function properly. A key regulator of energy balance is an enzyme known as 5' AMP-activated protein kinase (AMPK), which regulates the burning and storage of fuels such as fat and sugars, in response to changes in energy demand. This project will provide a major advancement in our understanding of the regulation of AMPK at the molecular level, and lay the foundations for the development of more effective drugs to treat energy balance disorders such as obesity and Type 2 diabetes. Furthermore, this proposal will contribute to enriching Australia's international profile and competitiveness in this important area of research.Read moreRead less
Correlative Structure-function Studies Of Cis- And Trans-Golgi Membrane Traffic In Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$649,531.00
Summary
This project combines imaging by light and electron microscopy with additional techniques for studying protein function at the molecular level, to elucidate how changes in the 3D organisation of cellular machinery can lead to fundamental changes in the function and health of mammalian cells. Although this work includes detailed investigation of the 'insulin factory', it has the potential to modify established concepts on membrane traffic and protein secretion well beyond the field of diabetes.
Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulat ....Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulation of a key copper pump, the Menkes protein, which helps control copper levels in the body and we are using the genetic advantages of the fruit fly Drosophila to discover new genes that regulate Menkes activity and therefore copper levels. These studies could lead to novel therapies for a range of copper-related disorders.Read moreRead less