Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test ....Molecular Mechanisms of NOD signalling. Alterations in NOD1 and NOD2 (nucleotide-binding oligomerization domain containing 1 and 2) signalling have been implicated in various human inflammatory diseases. Therefore, a clear understanding of the molecular signalling pathways is important to gain further insights into potential drug targets for the treatment of these diseases. Using novel experimental approaches, this project aims to identify new members of the NOD signalling pathway. It will test the effect of pharmacological inhibition of established molecules such as RIPK2 or IAPs in NOD dependent models for human diseases. Outcomes of this study will be of the utmost interest for the treatment of NOD driven diseases such as Crohn's disease, Blau syndrome or asthma.Read moreRead less
Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on rec ....Understanding endogenous allosteric modulators of G protein-coupled receptors. Major life science challenges include how chemicals outside cells signal to proteins inside, how this results in physiological responses, and how dysfunction of these processes leads to pathophysiology. Despite the critical importance of G protein-coupled receptors (GPCRs), much remains to be learned about their regulation by endogenous and synthetic molecules. This project aims to address this gap, by building on recent ground-breaking studies that have been performed, by focusing on alternative binding sites of GPCRs called allosteric sites. The major hypothesis is that these allosteric sites are widespread across GPCRs because the body produces endogenous allosteric ligands that remain largely unidentified, but which can play vital roles in biology.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE130100117
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Allosteric fingerprinting of G protein-coupled receptor monomers and oligomers. Allosteric modulation describes interactions between distinct, but conformationally linked, binding sites. Research will develop enabling technology using the unique profile, or 'fingerprint', of allosteric modulation at interacting and non-interacting G protein-coupled receptors to probe for receptor complexes within healthy and diseased tissue.
Structural and functional analysis of the protein kinase R. We have shown that protein kinase R (PKR) plays a key role in regulating the body's response to virus infections, inflammation and cancer. This project will identify mechanisms that regulate the activity of PKR and provide information useful for the development of novel drugs.
Exceptions Prove the Rule: How Antigen Recognition Drives T cell Activation. CD8+ T cells are immune cells that are critical for the adaptive immune response, which is central to immune function in vertebrates. CD8+ T cells mediate their effector functions only after activation, which occurs via T cell receptor (TCR) recognition of foreign antigens. Here, unique reagents and sophisticated technologies will be used to define precisely how the nature of TCR-antigen recognition impacts on T cell ac ....Exceptions Prove the Rule: How Antigen Recognition Drives T cell Activation. CD8+ T cells are immune cells that are critical for the adaptive immune response, which is central to immune function in vertebrates. CD8+ T cells mediate their effector functions only after activation, which occurs via T cell receptor (TCR) recognition of foreign antigens. Here, unique reagents and sophisticated technologies will be used to define precisely how the nature of TCR-antigen recognition impacts on T cell activation and effector function. This work builds on an earlier identification of an entirely novel mode of TCR-antigen recognition, and its success will establish novel paradigms in T cell biology and represent a key advance in knowledge in the life sciences.Read moreRead less
Modulating T cell responses with novel Lck activating compounds. Modulating T cell responses with novel Lck activating compounds. This project aims to research T cell receptor (TCR) signal initiation and network plasticity and identify uses for drugs that affect the kinase Lck. The TCR signalling network has considerable plasticity so that modulation of one molecule (here the drug target is Lck) can have non-linear effects on T cell function. This project intends to use novel drugs to understand ....Modulating T cell responses with novel Lck activating compounds. Modulating T cell responses with novel Lck activating compounds. This project aims to research T cell receptor (TCR) signal initiation and network plasticity and identify uses for drugs that affect the kinase Lck. The TCR signalling network has considerable plasticity so that modulation of one molecule (here the drug target is Lck) can have non-linear effects on T cell function. This project intends to use novel drugs to understand how the T cell network can be exploited to control both the magnitude and quality of the T cell responses. This research is expected to aid the design of immune-modulating drugs.Read moreRead less
Molecular mechanisms of cyclic Adenosine Monophosphate (AMP) induced apoptosis. Cyclic Adenosine Monophosphate (cAMP) is an important cellular chemical necessary for cell growth. However, de-regulated cAMP production in response to altered physiology can result in cellular death or apoptosis. This is attributed to the development of certain human diseases and this project aims to understand the molecular mechanism behind this process.
A molecular investigation into the naïve T cell repertoire. This project aims to interrogate the relationship between T cell receptor (TCR) recognition modes and T cell recruitment and activation. CD8+ T cells are important for adaptive immunity. Their recognition, via TCR, of peptides bound to MHC class I antigen-presenting molecules (pMHCI), initiates a signalling cascade which activates T cells effector functions. All structural information on TCR recognition of pMHCI is based on TCRs prevale ....A molecular investigation into the naïve T cell repertoire. This project aims to interrogate the relationship between T cell receptor (TCR) recognition modes and T cell recruitment and activation. CD8+ T cells are important for adaptive immunity. Their recognition, via TCR, of peptides bound to MHC class I antigen-presenting molecules (pMHCI), initiates a signalling cascade which activates T cells effector functions. All structural information on TCR recognition of pMHCI is based on TCRs prevalent in immune responses, and all recognise pMHCI using a conserved orientation. This project aims to use this observation to study the relationship between TCR recognition modes and T cell recruitment and activation.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100149
Funder
Australian Research Council
Funding Amount
$300,000.00
Summary
CyTOF platform for the Advanced Cytometry Facility: overcoming fluorescence spectral barriers to truly multiparametric cytometry by mass spectrometry. Cytometry by time-of-flight mass spectrometry platform for the Advanced Cytometry Facility: overcoming fluorescence spectral barriers to truly multiparametric cytometry by mass spectrometry: This project will provide a flow cytometer capable of analysing single cells by time-of-flight mass spectrometry. Antibody labels for cell components will ena ....CyTOF platform for the Advanced Cytometry Facility: overcoming fluorescence spectral barriers to truly multiparametric cytometry by mass spectrometry. Cytometry by time-of-flight mass spectrometry platform for the Advanced Cytometry Facility: overcoming fluorescence spectral barriers to truly multiparametric cytometry by mass spectrometry: This project will provide a flow cytometer capable of analysing single cells by time-of-flight mass spectrometry. Antibody labels for cell components will enable measurement of up to 100 parameters/cell. Developing analytical and modelling algorithms like Spanning tree Progression of Density normalised Events (SPADE), this project will aim to map the relationships of various unelucidated cell lineages, via functional pathway connections. New pathways thus revealed will enable elaboration and use of novel specific molecules in perturbational analyses to confirm and further enhance the understanding of these highly intricate, basic relationships. This will provide unparalleled insight, both into early development of stem cells and mechanisms of maintenance of homeostasis in differentiated cells.Read moreRead less
Evolution of immunoregulatory networks: preventing autoimmunity at the expense of perpetuating chronicity in persistent infections. Chronic pathogens like HIV take advantage of human genes that regulate immune responses, which evolved to prevent autoimmunity, enabling them to evade eradication. This project defines the nature and interplays between these genes and will provide valuable clues as to how immunity can be manipulated to promote clearance of persistent infections.