Discovery Early Career Researcher Award - Grant ID: DE230101681
Funder
Australian Research Council
Funding Amount
$457,139.00
Summary
Cryo-electron microscopy determination of G protein-coupled receptor states. This project aims to address fundamental knowledge gaps in understanding of the molecular mechanisms of peptide hormone G protein-coupled receptor activation. This will be achieved through cryo-electron microscopy determination of the structure and dynamics of key intermediate states in activation. Novel biochemical approaches will be applied to capture these states, using as exemplar the glucagon receptor that has a br ....Cryo-electron microscopy determination of G protein-coupled receptor states. This project aims to address fundamental knowledge gaps in understanding of the molecular mechanisms of peptide hormone G protein-coupled receptor activation. This will be achieved through cryo-electron microscopy determination of the structure and dynamics of key intermediate states in activation. Novel biochemical approaches will be applied to capture these states, using as exemplar the glucagon receptor that has a broad range of pharmacological tools to facilitate isolation of distinct functional states. The knowledge gained from these studies will advance fundamental understanding of physiologically important receptor activation and efficacy, while the approaches developed will enable similar investigation of other receptor classes.Read moreRead less
Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SF ....Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SFV greatly perturbs T cell dynamics. This proposal will study, at cellular and molecular levels, T cell trafficking, function and clonal distribution during antigenic interference, thus advance fundamental knowledge on T cell immunity during antigenic competition, and provide a new paradigm on how we research T cell immunity.Read moreRead less
The Role of Lck/CD8 Association in Negatively Regulating T cell Activation. This proposal aims to advance our fundamental understanding of how T cell recognition of antigens translates into a T cell activating signal. The proposal will establish whether the major T cell coreceptor also acts as a negative regulator of T cell activation in vivo when antigen recognition is unorthodox. It will also determine whether certain subsets of T cells naturally lack coreceptors in order to facilitate unortho ....The Role of Lck/CD8 Association in Negatively Regulating T cell Activation. This proposal aims to advance our fundamental understanding of how T cell recognition of antigens translates into a T cell activating signal. The proposal will establish whether the major T cell coreceptor also acts as a negative regulator of T cell activation in vivo when antigen recognition is unorthodox. It will also determine whether certain subsets of T cells naturally lack coreceptors in order to facilitate unorthodox antigen recognition. Thus, the proposal will significantly advance our understanding of, and establish new paradigms around, the regulation of T cell activation. Expected long term benefits outside the scope of this proposal include improved immunotherapies and vaccines designed to elicit or suppress T cell responses.Read moreRead less
How do cytokine receptors transmit signals? This project aims to determine the mechanisms of signal transmission by cytokine receptors using state-of-the-art microscopy techniques. Cytokines are small proteins that act as messengers between cells and play fundamental roles in biology. Cytokines bind to receptors on the surface of cells, producing a response within the cells. Yet, how the message is transmitted across the cell membrane is not well understood. Expected outcomes of this project inc ....How do cytokine receptors transmit signals? This project aims to determine the mechanisms of signal transmission by cytokine receptors using state-of-the-art microscopy techniques. Cytokines are small proteins that act as messengers between cells and play fundamental roles in biology. Cytokines bind to receptors on the surface of cells, producing a response within the cells. Yet, how the message is transmitted across the cell membrane is not well understood. Expected outcomes of this project include discovery of mechanisms general to cytokine signalling and new approaches to investigate cytokine biology. This new knowledge will benefit efforts to understand and modulate cytokine signalling in animals and humans, with future impacts in the agriculture, veterinary, and health sectors.Read moreRead less
New mechanisms regulating the biogenesis of extracellular vesicles. Extracellular vesicles are small packages that contain active components derived from the cell of origin. These vesicles, released by most cell types, are critical for communication between cells. However, the processes of their formation and release remain poorly understood. This project aims to explore how ubiquitination, a type of protein modification system, controls the production of extracellular vesicles. Using a strong c ....New mechanisms regulating the biogenesis of extracellular vesicles. Extracellular vesicles are small packages that contain active components derived from the cell of origin. These vesicles, released by most cell types, are critical for communication between cells. However, the processes of their formation and release remain poorly understood. This project aims to explore how ubiquitination, a type of protein modification system, controls the production of extracellular vesicles. Using a strong collaborative team and highly innovative approaches, the project will generate new knowledge to inform how cells communicate. Expected outcomes include knowledge of broad significance to cell biology, that can be leveraged to develop extracellular vesicles as tools for various biotechnology applications in the future.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE240100931
Funder
Australian Research Council
Funding Amount
$453,237.00
Summary
Molecular insights into the allosteric regulation of opioid receptors. Allosteric regulation is the biological process by which molecules bind to proteins someplace other than their active site, regulating their activity. Proteins on the cell surface called membrane receptors can be allosterically regulated to fine-tune the response of cells to the environment. This project aims to investigate how small molecules regulate receptor activity at a molecular level, using opioid receptors as an exemp ....Molecular insights into the allosteric regulation of opioid receptors. Allosteric regulation is the biological process by which molecules bind to proteins someplace other than their active site, regulating their activity. Proteins on the cell surface called membrane receptors can be allosterically regulated to fine-tune the response of cells to the environment. This project aims to investigate how small molecules regulate receptor activity at a molecular level, using opioid receptors as an exemplar system. I will use an interdisciplinary approach that combines structural biology, medicinal chemistry, analytical pharmacology, and cell biology. The knowledge gained from these studies will advance fundamental understanding of receptor function and can lay the foundation for future drug discovery efforts.Read moreRead less
In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-ski ....In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-skilled techniques, including cryo-electron microscopy and single-molecule imaging and holds ancillary benefits to postgraduate students. Anticipated outcomes include influential publications, building a critical mass of expertise in Australia and fostering international collaborations with Australia at the epicentre.Read moreRead less
Beyond structure - solving conformational dynamics for intractable proteins. Proteins perform almost every task that enables the amazing complexity of cellular and whole organism physiology. These molecular machines perform this incredible array of tasks due to their ability to dynamically change shape. For the vast majority of these machines, we can only view a snapshot of the possible shapes they can adopt and can’t monitor how they change from one shape to another, which is critical for their ....Beyond structure - solving conformational dynamics for intractable proteins. Proteins perform almost every task that enables the amazing complexity of cellular and whole organism physiology. These molecular machines perform this incredible array of tasks due to their ability to dynamically change shape. For the vast majority of these machines, we can only view a snapshot of the possible shapes they can adopt and can’t monitor how they change from one shape to another, which is critical for their functioning. This project aims to develop and apply a completely new method to visualise dynamic changes in protein shape which is not possible with current techniques. This will allow us to provide a new description and understanding of the function of proteins, which is fundamental to all biology.Read moreRead less
Structure and dynamics of class B1 G protein coupled receptors . Cells within our body require cell surface proteins (receptors) to convert extracellular stimuli into an appropriate biological response. G protein-coupled receptors are the largest group of cell surface receptors. This project focuses on a subset of these receptors that have diverse and important functions in the central nervous system and the periphery, however there are many unanswered questions regarding the structure of these ....Structure and dynamics of class B1 G protein coupled receptors . Cells within our body require cell surface proteins (receptors) to convert extracellular stimuli into an appropriate biological response. G protein-coupled receptors are the largest group of cell surface receptors. This project focuses on a subset of these receptors that have diverse and important functions in the central nervous system and the periphery, however there are many unanswered questions regarding the structure of these proteins, and how they regulate cellular signalling. The primary outcomes of this project will provide detailed mechanistic insights on how receptors bind their stimuli and how this results in in their activation to mediate fundamental signalling that is important for all living organisms.Read moreRead less