Macrophage Polarisation And Control Of Pulmonary Inflammation.
Funder
National Health and Medical Research Council
Funding Amount
$895,494.00
Summary
As key immune cells, macrophages are polarised to phenotypes that turn inflammation on or off. In cystic fibrosis, defective macrophage polarisation enhances inflammation and prevents lung repair. We are defining the molecules and cellular pathways that control this process and identifying targets for existing drugs that can be used to reprogram macrophages and restore lung repair to improve patient outcomes.
A New Master Adaptor Protein For Toll-like Receptor Signalling
Funder
National Health and Medical Research Council
Funding Amount
$869,288.00
Summary
Certain proteins on the surface of cells are able to sense danger and infection. These receptors use adaptor proteins to enable cells to respond appropriately. We have discovered a new adaptor that controls receptor signalling in inflammation. This new master adaptor likely has widespread roles in infection and inflammation. We aim to understand how this adaptor works, and to identify ways of blocking its actions. These studies may help us to control inflammation underpinning many diseases.
Innate Immune Signalling In Mycobacterium Tuberculosis Infection
Funder
National Health and Medical Research Council
Funding Amount
$562,857.00
Summary
Tuberculosis (TB) is a major global health threat that causes 1.5 million deaths every year. This study will characterise a new molecular control mechanism that optimises the immune response to the bacteria that cause TB and determine how it contributes to controlling the infection. Such knowledge is essential to help improve patient management and develop better treatments for this devastating disease.
Macrophages are important cells at the front-line of immunity where one of their main roles is to release anti-bacterial proteins. We will study the macrophage molecules, subcellular organelles and pathways that help to release these proteins to kill bacteria and fight infection. Our studies will identify new cellular targets for boosting immunity and treating inherited diseases with defective macrophage function.
Understanding the molecular mechanisms regulating neuronal fusion. Neurons are tightly connected individual cells that communicate through chemical and electrical signals, and this project aims to discover the key molecules that allow these cells to remain as individual units without fusing with each other. The nervous system, unlike other tissues, is made of discrete individual cells, connected by chemical and electrical synapses but not by cytoplasmic continuity. However, how this is achieved ....Understanding the molecular mechanisms regulating neuronal fusion. Neurons are tightly connected individual cells that communicate through chemical and electrical signals, and this project aims to discover the key molecules that allow these cells to remain as individual units without fusing with each other. The nervous system, unlike other tissues, is made of discrete individual cells, connected by chemical and electrical synapses but not by cytoplasmic continuity. However, how this is achieved and how neurons maintain their individuality during development, remodelling and ageing is unknown. The project aims to address this gap using a genetic approach and the nematode Caenorhabditis elegans as an experimental system. The results may provide insights into how the nervous system develops and functions.Read moreRead less
Interactions between phenome and genome at developing CNS synapses during synaptic refinement. Activity-dependent changes in synaptic transmission are vital to development and function of central neuronal networks. However, the critical factors regulating developmental changes in synaptic signals remain largely unknown. We will correlate functional changes in synaptic responses at glutamate-releasing synapses with changes in glutamate receptor composition at a critical period during developmen ....Interactions between phenome and genome at developing CNS synapses during synaptic refinement. Activity-dependent changes in synaptic transmission are vital to development and function of central neuronal networks. However, the critical factors regulating developmental changes in synaptic signals remain largely unknown. We will correlate functional changes in synaptic responses at glutamate-releasing synapses with changes in glutamate receptor composition at a critical period during development, test whether synaptic activation of receptors is required for these changes and define the pattern of activity-dependent changes in gene expression necessary for developmental changes in synaptic transmission. Understanding this interaction between synaptic phenome and activity-dependent genomic expression will expand our understanding of brain development and function.Read moreRead less
Development of novel reagents that specifically counteract EphA4 to enhance axonal regeneration. This project will examine the role of EphA4, an important guidance protein, in neural cell regeneration. The goal is to understand the signalling mechanisms that inhibit regeneration in the central nervous system and to develop novel biological agents to overcome these processes and promote functional recovery after nervous system injury or disease.
Click chemistry to reveal how neurons and glia shape perineuronal nets . The extracellular matrix (ECM) and its perineuronal nets (which are net-like structures with holes wrapped around neurons) are largely underexplored, despite representing a remarkable 20% of the brain’s total volume and having been suggested to be involved in many brain functions. Interestingly, digestion of the ECM improves learning and memory, but deficits return once the ECM has reformed. However, how this ECM remodellin ....Click chemistry to reveal how neurons and glia shape perineuronal nets . The extracellular matrix (ECM) and its perineuronal nets (which are net-like structures with holes wrapped around neurons) are largely underexplored, despite representing a remarkable 20% of the brain’s total volume and having been suggested to be involved in many brain functions. Interestingly, digestion of the ECM improves learning and memory, but deficits return once the ECM has reformed. However, how this ECM remodelling is organised at a cell-type level is not understood. Here we aim to close this knowledge gap, using cutting-edge technology including bioconjugation and ultrasound-mediated cargo delivery. Together, this project aims to contribute to a deeper understanding of this major brain compartment in neuronal function. Read moreRead less
Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much ac ....Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much acclaimed and novel pathway that allows efficient, combined cytokine secretion and phagocytosis in macrophages. Our studies proposed here will now expand on this discovery by comparing the phagocytic process, in terms of SNARE-mediated membrane and cytokine trafficking, for a wide range of microbes, highlighting differences that could provide new avenues for drug development. Moreover, since our strategy of using SNAREs to investigate and map trafficking pathways has proven so successful, we will now launch a major large-scale initiative to study ALL SNARE-mediated trafficking pathways in macrophages using a discovery pipeline of assays, including live cell imaging, we have developed. This will provide valuable information on many SNAREs including those associated with disease, and will elucidate trafficking pathways governing all macrophage actions in immunity, including cytokine secretion and antigen presentation. All of these pathways are highly relevant to current drug targets being used clinically or studied in inflammatory disease and for the development of vaccines.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE230100998
Funder
Australian Research Council
Funding Amount
$444,576.00
Summary
Should I stay or should I go? How brain stem cells leave quiescence. Most adult stem cells in our brains are sleeping (quiescent). Quiescence helps ensure animals have a lifelong population of brain stem cells, which is crucial for the maintenance of brain circuitry. This project aims to investigate how this process is regulated at a molecular level. This project expects to define the molecular playbook controlling quiescence and explain why brain stem cells progress into deeper states of quiesc ....Should I stay or should I go? How brain stem cells leave quiescence. Most adult stem cells in our brains are sleeping (quiescent). Quiescence helps ensure animals have a lifelong population of brain stem cells, which is crucial for the maintenance of brain circuitry. This project aims to investigate how this process is regulated at a molecular level. This project expects to define the molecular playbook controlling quiescence and explain why brain stem cells progress into deeper states of quiescence during aging by combining novel tissue culture and genetic models, where brain stem cells have disrupted quiescence, with innovative methods of reading gene expression. The benefits of these outcomes include the development of methods to control the quiescence of brain stem cells for bioengineering purposes.Read moreRead less