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
Characterisation Of Novel CDKL5 Targets: Implications For Rett Syndrome And Related Neurodevelopmental Disorders.
Funder
National Health and Medical Research Council
Funding Amount
$421,977.00
Summary
Rett syndrome (RTT) is the second most common cause of severe mental retardation in girls and women. Although two genes (MECP2 and CDKL5) responsible for RTT have been identified, we still do not understand how these genes affect brain function. The focus of this research project is to identify which proteins are controlled by CDKL5, with the express hope that a better understanding of these processes will allow us to design specfic therapies for this untreatable devasting disorder.
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
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.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
Regulation Of Body Composition And Glucose Homeostasis By The Adaptor Protein Grb10.
Funder
National Health and Medical Research Council
Funding Amount
$617,256.00
Summary
Resistance to the hormone insulin underlies the development of Type 2 Diabetes. Loss of muscle mass in the elderly contributes to insulin resistance. Recently we identified Grb10 as a new regulator of insulin action and muscle mass. In this proposal, we aim to study how Grb10 affects development and growth of muscle and fat, and the underlying molecular mechanisms. This may lead to new strategies for improving body composition and treating the insulin resistance associated with Type 2 Diabetes.
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