Discovery Early Career Researcher Award - Grant ID: DE180100418
Funder
Australian Research Council
Funding Amount
$365,058.00
Summary
Novel chemical tools to study cathepsin X activation. This project aims to develop new chemical tools that can measure the specific activation of cathepsin X in cells, tissues, and live animals, as well as specific inhibitors for cathepsin X. The cysteine protease cathepsin X mediates basic biological functions that are essential for life, including cell communication, phagocytosis, immune maturation and neuritogenesis. The outcomes should benefit the wider research community. They could have lo ....Novel chemical tools to study cathepsin X activation. This project aims to develop new chemical tools that can measure the specific activation of cathepsin X in cells, tissues, and live animals, as well as specific inhibitors for cathepsin X. The cysteine protease cathepsin X mediates basic biological functions that are essential for life, including cell communication, phagocytosis, immune maturation and neuritogenesis. The outcomes should benefit the wider research community. They could have long-term implications for health and disease, and deliver economic benefits through commercialisation of the novel tools.Read moreRead less
Regulation Of Pre-mRNA And MRNA Processing By The Neuron-specific Hu RNA-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, t ....The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, this activation is just the start of the process to produce an active protein. In higher organisms, these RNA copies almost always contain interruptions called introns, which must be excised from the RNA. Also, protein factors bound to specific RNAs can dictate whether the RNA is used to make protein or not, and these factors can also affect the localisation of the RNA to a specific sub-cellular destination, giving rise to highly localised protein expression. Evidence suggests that neurons are a cell type that rely heavily on mechanisms of RNA regulation. During development neurons become highly polarised, acquiring an axon which can elongate and find distant synaptic targets. While much is known about how axon growth cones respond to various guidance cues, the mechanisms by which the axon is able to translate this guidance cue information into structural changes which allow the growth cone to expand or collapse is largely unexplored. Recent evidence suggests that accurate growth cone guidance is absolutely dependent upon local protein synthesis. The functional corollary of this finding is that axon guidance requires RNA localisation and control of protein synthesis of RNAs in the growth cone. This phenomenon of spatial gene regulation within an individual cell is a central research interest for understanding how the brain functions.Read moreRead less
Biosynthesis and functions of two phytotoxins in Septoria nodorum blotch. This project aims to investigate how a fungal plant pathogen makes and uses small bioactive molecules to facilitate infection. It will characterise the function of the genes and enzymes involved in the biosynthesis of a light-activated phytotoxic molecule and a potential anti-plant defence molecule found in the pathogenic wheat fungus Parastagonospora nodorum, and investigate their contribution to disease development. Expe ....Biosynthesis and functions of two phytotoxins in Septoria nodorum blotch. This project aims to investigate how a fungal plant pathogen makes and uses small bioactive molecules to facilitate infection. It will characterise the function of the genes and enzymes involved in the biosynthesis of a light-activated phytotoxic molecule and a potential anti-plant defence molecule found in the pathogenic wheat fungus Parastagonospora nodorum, and investigate their contribution to disease development. Expected outcomes include better understanding of plant-microbe interactions, disease management strategies, technologies for identifying biosynthetic pathways in other fungi, and enzyme technology for synthesising molecules. This could lead to new herbicides, biopesticides and drugs.Read moreRead less
Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacte ....Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacteria, and a richer understanding of how these proteins have evolved over the last 4 billion years. This promises significant benefits in the form of new ways to address the challenge posed by antimicrobial resistance to antibiotics, which is a serious threat to the continued effectiveness of current antibiotics.Read moreRead less
Fungal Ribosomally Synthesised and Post-translationally Modified Peptides. Fungi produce an array of molecules called secondary metabolites (SMs) that impact on everyday life (e.g. penicillin). This project aims to investigate a new class of fungal peptide SMs called RiPPs which are structurally unique from existing molecules and offer the exciting prospect of harbouring new and novel biological activities. This project expects to discover the mechanisms of RiPP synthesis and their biological ro ....Fungal Ribosomally Synthesised and Post-translationally Modified Peptides. Fungi produce an array of molecules called secondary metabolites (SMs) that impact on everyday life (e.g. penicillin). This project aims to investigate a new class of fungal peptide SMs called RiPPs which are structurally unique from existing molecules and offer the exciting prospect of harbouring new and novel biological activities. This project expects to discover the mechanisms of RiPP synthesis and their biological roles in plant pathogenic fungi, and uncover and engineer novel RiPPs with desired bioactivities. The expected outcome from this project will be a seminal advance in fungal SM biology which should provide significant benefits through the generation of exciting new lead molecules for the agricultural and medical industries.Read moreRead less
Allosteric and Bitopic Ligands Acting at G Protein-Coupled Receptors. This project seeks to gain a more detailed understanding of the mechanisms of the function of G protein-coupled receptors (GPCRs) using novel chemical tools. GPCRs are the largest group of cell surface signalling proteins and are responsible for the regulation of numerous vital physiological functions. They are the target of over 30 per cent of currently used pharmaceuticals. Despite their importance, much remains to be learne ....Allosteric and Bitopic Ligands Acting at G Protein-Coupled Receptors. This project seeks to gain a more detailed understanding of the mechanisms of the function of G protein-coupled receptors (GPCRs) using novel chemical tools. GPCRs are the largest group of cell surface signalling proteins and are responsible for the regulation of numerous vital physiological functions. They are the target of over 30 per cent of currently used pharmaceuticals. Despite their importance, much remains to be learned about the regulation of GPCRs by small molecules. This project aims to address this gap by focusing on novel regions on these proteins, termed allosteric sites, to explore novel modes of GPCR regulation which may offer the potential of identifying pathway selective agents.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170100058
Funder
Australian Research Council
Funding Amount
$372,000.00
Summary
Molecular reporters for measuring proteostasis capacity in cells. This project aims to develop fluorescent dyes to report on the change in unfolded protein load, which reflects the proteostasis status in real time in cells under stress conditions. Proteostasis is a housekeeping process cells undertake to maintain the proper folding and functions of proteins. Perturbation of proteostasis has been linked to neurodegenerative diseases, but chemical probes cannot measure the proteostasis capacity in ....Molecular reporters for measuring proteostasis capacity in cells. This project aims to develop fluorescent dyes to report on the change in unfolded protein load, which reflects the proteostasis status in real time in cells under stress conditions. Proteostasis is a housekeeping process cells undertake to maintain the proper folding and functions of proteins. Perturbation of proteostasis has been linked to neurodegenerative diseases, but chemical probes cannot measure the proteostasis capacity in cells. Intended outcomes include a mechanistic understanding of the relationship between protein misfolding, aggregation and proteostasis. This is expected to ultimately benefit the diagnosis of protein folding diseases, including dementia, and improve the quality of life.Read moreRead less
MRNA Surveillance In Human Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types o ....Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types of mutations, one relatively common type is called a premature termination mutation. Premature termination mutations introduce an inappropriate genetic signal that tells the cells to stop the formation of proteins before they are complete. This would result in the production of a protein that is shorter than normal, and these short proteins could be quite abnormal and drastically affect the normal function of cells. To overcome this, cells have developed elegant strategies that involve the deployment of quality control, or surveillance, mechanisms to remove the mutant gene product before it can be converted into an abnormal protein. This process is called nonsense mediated decay. Nonsense mediated decay is a complex process and some of the key components have been identified by studies on a small number of genes. However, our studies have identified several previously unknown aspects of the process that suggest that the currently held view of how nonsense mediated decay works is only the beginning of the story and further important complexity exists. The proposed research will explore the basic mechanisms of the surveillance process and determine the signals that initiate nonsense mediated decay. Since premature termination mutations cause one-third of all inherited genetic disorders, our studies will provide new insights into the surveillance mechanisms and will have wide applicability to our understanding of the basis of inherited disease.Read moreRead less
CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project ....CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project will develop innovative new methods to "hot-wire" these genes, allowing them to turn on and produce a treasure trove of new bioactive molecules. The outcomes of this project will transform our abilities to tap into the hidden potential of fungi to generate new lead molecules for the agricultural and medical industries.Read moreRead less