The Role Of C-reactive Protein (CRP) In Localising Inflammation To Misfolded Proteins And “stressed” Cells: A Basis For The Development Of New Anti-inflammatory Reagents?
Funder
National Health and Medical Research Council
Funding Amount
$723,488.00
Summary
Many diseases are exacerbated by inflammatory reactions. We describe how a protein circulating in the blood is a major driver of inflammatory reactions and how it is transformed from an inactive state to an active, highly pro-inflammatory state. Our project aims to understand how this transformation occurs at the molecular level, and to develop diagnostic techniques and innovative drugs to treat diseases such as heart attack, Alzheimer’s disease and other inflammatory diseases.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100016
Funder
Australian Research Council
Funding Amount
$850,000.00
Summary
A collaborative electron microscopy network for structural biology. This project aims to establish a high-throughput pipeline to determine the near-atomic-resolution structure of proteins by cryo-electron microscopy (cryo-EM). Over the past five years, cryo-EM has improved the study of biological macromolecules at near-atomic resolution. This project will use two automated electron microscopes and a Titan Krios microscope to build a world-competitive integrated cryo-EM network for structural bio ....A collaborative electron microscopy network for structural biology. This project aims to establish a high-throughput pipeline to determine the near-atomic-resolution structure of proteins by cryo-electron microscopy (cryo-EM). Over the past five years, cryo-EM has improved the study of biological macromolecules at near-atomic resolution. This project will use two automated electron microscopes and a Titan Krios microscope to build a world-competitive integrated cryo-EM network for structural biology. This research is expected to increase the understanding of molecular events that are central for life.Read moreRead less
Molecular basis for control of DNA transcription of housekeeping genes. This project aims to understand how 90 per cent of all eukaryotic genes are regulated. The development of a multicellular organism needs thousands of different messenger RNAs, at exactly the right time, in the right set of cells and in the right amount, creating a need for stringent regulation of gene expression. The data generated by the project will show how a massive protein complex of ~50 individual gene products—the gen ....Molecular basis for control of DNA transcription of housekeeping genes. This project aims to understand how 90 per cent of all eukaryotic genes are regulated. The development of a multicellular organism needs thousands of different messenger RNAs, at exactly the right time, in the right set of cells and in the right amount, creating a need for stringent regulation of gene expression. The data generated by the project will show how a massive protein complex of ~50 individual gene products—the general transcription machinery—identifies a gene’s start site, recruits RNA polymerase II and prepares it for transcription of the genetic code. The project is expected to reveal the molecular basis of a process that is as important for flowering in plants as it is for embryonic development in metazoans.Read moreRead less
Undermining fungal defences by targeting their functional amyloid armour. This project will determine how a protective protein coating forms on the surface of fungal spores and infectious structures. This coating is comprised of amyloid protein fibrils and is used by fungi to improve efficiency of infection and to avoid detection by the host plant or animal. We have discovered novel small molecules that prevent the fibrils from forming. This project will use these molecules to reveal the details ....Undermining fungal defences by targeting their functional amyloid armour. This project will determine how a protective protein coating forms on the surface of fungal spores and infectious structures. This coating is comprised of amyloid protein fibrils and is used by fungi to improve efficiency of infection and to avoid detection by the host plant or animal. We have discovered novel small molecules that prevent the fibrils from forming. This project will use these molecules to reveal the details of the fibril assembly mechanism and find the best way to undermine this fungal defence system. This knowledge will enable the development of potent small molecule inhibitors to treat fungal infections that blight crops and harm animals, and the production of new layered biomaterials for nanotechnology applications.Read moreRead less
New approaches to inhibition of activity of HIV integrase. This project aims to assist in the development of novel anti-HIV drugs that will benefit the 17000 Australians and more than 33 million people worldwide who are currently suffering with this terrible disease. The project will utilise state-of-the-art approaches in structure-based drug design to identify and synthesise compounds as leads for the development of anti-HIV drugs. Furthermore, the project will provide invaluable training for t ....New approaches to inhibition of activity of HIV integrase. This project aims to assist in the development of novel anti-HIV drugs that will benefit the 17000 Australians and more than 33 million people worldwide who are currently suffering with this terrible disease. The project will utilise state-of-the-art approaches in structure-based drug design to identify and synthesise compounds as leads for the development of anti-HIV drugs. Furthermore, the project will provide invaluable training for the researchers involved and enhance the relationship between the academic and commercial collaborators.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE190100304
Funder
Australian Research Council
Funding Amount
$416,092.00
Summary
Understanding intramolecular regulation of ubiquitin enzymes. This project aims to combine structural, biophysical and functional studies to characterise how ubiquitin enzymes are regulated. Ubiquitination controls essential cellular pathways in all eukaryotes and this project expects to generate new knowledge regarding the vital regulation of this process. This project expects to develop broadly applicable techniques for investigating protein conformation and self-association as a means of cont ....Understanding intramolecular regulation of ubiquitin enzymes. This project aims to combine structural, biophysical and functional studies to characterise how ubiquitin enzymes are regulated. Ubiquitination controls essential cellular pathways in all eukaryotes and this project expects to generate new knowledge regarding the vital regulation of this process. This project expects to develop broadly applicable techniques for investigating protein conformation and self-association as a means of controlling catalytic activity. The project should significantly increase understanding of several modes of regulation of ubiquitin ligase catalytic activity, and how this controls a myriad of cellular processes. The project will lay the foundation for applied research anti-viral compounds, plant anti-fungals and cancer therapies.Read moreRead less
A new source of bivalent molecules from nature. This project aims to describe a new class of naturally occurring multivalent molecules termed secreted cysteine-rich repeat proteins (SCREPs). Multivalency is a key feature of molecular interaction in biology, underlying the high specificity and potency found in many proteins. Focusing on bivalent peptides, the project will generate a database of bioactive SCREPs with similarity to known bioactive peptides, and develop new recombinant methods for t ....A new source of bivalent molecules from nature. This project aims to describe a new class of naturally occurring multivalent molecules termed secreted cysteine-rich repeat proteins (SCREPs). Multivalency is a key feature of molecular interaction in biology, underlying the high specificity and potency found in many proteins. Focusing on bivalent peptides, the project will generate a database of bioactive SCREPs with similarity to known bioactive peptides, and develop new recombinant methods for their production. The project will use advanced nuclear magnetic resonance spectroscopy to characterise members of this new class, providing new insights into the design of bivalent and multivalent peptides and establishing a new source of molecules with applications in the rapidly growing biotechnology sector.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170100783
Funder
Australian Research Council
Funding Amount
$372,000.00
Summary
Structural basis of paramyxovirus host cell entry. This project aims to investigate interactions between paramyxoviruses and host cell receptors and the mechanisms underlying fusion activation at a molecular level. Paramyxoviruses include economically important human and animal pathogens. Two viral proteins are key to infection: an attachment protein for the interaction with host receptors, and a fusion protein for fusion of viral and cellular membranes. The project is anticipated to discover ge ....Structural basis of paramyxovirus host cell entry. This project aims to investigate interactions between paramyxoviruses and host cell receptors and the mechanisms underlying fusion activation at a molecular level. Paramyxoviruses include economically important human and animal pathogens. Two viral proteins are key to infection: an attachment protein for the interaction with host receptors, and a fusion protein for fusion of viral and cellular membranes. The project is anticipated to discover general principles of how paramyxoviruses infect host cells, which should advance fundamental understanding of viral infection strategies and may identify strategies for rational design of inhibitors targeting host-cell entry of multiple paramyxoviruses.Read moreRead less
Understanding the molecular basis of heparanase activity. This project aims to advance our understanding of the structure and impact on biological processes of heparanase (HSPE), an enzyme of critical importance. HSPE’s ability to interact with heparan sulfate (HS), a key component of the extracellular matrix and basement membranes, makes HPSE a pivotal enzyme in many important physiological and disease-related processes ranging from angiogenesis, tumour metastasis, inflammation, hair follicle ....Understanding the molecular basis of heparanase activity. This project aims to advance our understanding of the structure and impact on biological processes of heparanase (HSPE), an enzyme of critical importance. HSPE’s ability to interact with heparan sulfate (HS), a key component of the extracellular matrix and basement membranes, makes HPSE a pivotal enzyme in many important physiological and disease-related processes ranging from angiogenesis, tumour metastasis, inflammation, hair follicle development to wrinkle formation. The knowledge gained through this project is expected to provide new insight into the interaction between HSPE and HS/HSPG to reveal new pathways to the development of inhibitors to treat diseases such as cancer and diabetes.Read moreRead less
Exploring the novel structural features of influenza virus sialidase. The outcomes of this project will provide a deeper mechanistic understanding of influenza virus sialidase and the importance of the enzyme's flexible loops in carbohydrate recognition. Specifically, this project will improve our understanding of fundamental aspects of inhibitor binding by influenza virus sialidases.