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Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition ....Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition their site of lodgement to best harness their potential. This project aims to address these issues. We have recently identified a rare population of cells in the adult mouse lung which has a number of characteristics consistent with that of an adult stem cell. We are able to grow these cells in tissue culture, and we have preliminary data suggesting that they can regenerate lung tissue when transplanted. The aim of this project is to precisely identify these cells, develop methods for their isolation and determine their location in the lung. The assays we will develop in this model will then be used to identify stem cells in the bone marrow which have similar properties and which could potentially be used clinically to alleviate lung disease. The project brings together a group of investigators with unique expertise in the isolation and analysis of adult stem cells, and in clinical and experimental respiratory medicine to develop preclinical models in the mouse which are prerequisite for the developement and implementation of step cell based therapies for lung disease in humans.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170100226
Funder
Australian Research Council
Funding Amount
$372,000.00
Summary
How innate lymphoid cells regulate mammalian lung development. This project aims to determine the ability of a subset of lung resident immune cells to promote normal lung development through the regulation of stem cells. The lung is constantly exposed to countless environmental challenges including microbes. Mammals’ local immune systems protect the lung from these challenges. This is particularly important in early-life when the lung is still developing. However, impaired lung development affec ....How innate lymphoid cells regulate mammalian lung development. This project aims to determine the ability of a subset of lung resident immune cells to promote normal lung development through the regulation of stem cells. The lung is constantly exposed to countless environmental challenges including microbes. Mammals’ local immune systems protect the lung from these challenges. This is particularly important in early-life when the lung is still developing. However, impaired lung development affects humans and livestock, costing >$3 billion p.a. The intended outcome is to identify basic biological processes involved in normal mammalian lung development, which may lead to strategies to prevent chronic lung diseases in humans and animals.Read moreRead less
Control Of CD4 Function By Disulphide-Bond Switching
Funder
National Health and Medical Research Council
Funding Amount
$252,761.00
Summary
CD4 is a cell-surface protein that has two functions in the human body, a good one and a bad one. Its good function is as a checkpoint for development of the immune system and for response of the immune system to infection. It helps immune cells known as T cells to recognize and dispose of a foreign particle in the body. Its bad function is that it is one of two proteins that enable the HIV virus to enter and destroy immune cells. The HIV virus binds to CD4 on immune cells, which leads to fusion ....CD4 is a cell-surface protein that has two functions in the human body, a good one and a bad one. Its good function is as a checkpoint for development of the immune system and for response of the immune system to infection. It helps immune cells known as T cells to recognize and dispose of a foreign particle in the body. Its bad function is that it is one of two proteins that enable the HIV virus to enter and destroy immune cells. The HIV virus binds to CD4 on immune cells, which leads to fusion of the viral and immune cell surfaces and entry of the virus into the cell. Once inside the immune cell the virus reproduces itself and goes on to kill more immune cells. AIDS results when too many immune cells are killed. We have discovered that CD4 exists in three different forms on the immune cell surface; an oxidized, reduced or dimeric form. These different forms result from a molecular switch we discovered in CD4. We have suggested that the good and bad functions of CD4 are mediated by different forms of CD4. The good function is mediated by dimeric CD4, while the bad function is mediated by reduced CD4. The purpose of this application is to test this hypothesis. If we are correct then our findings will have significant implications for our understanding of how the immune system responds to a foreign invader and how HIV-AIDS destroys the immune system. This knowledge could be used to develop drugs that suppress the immune system when required, such as in organ transplantation, and that fight HIV-AIDS.Read moreRead less
Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor in ....Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor involved in the generation of bacterial virulence. This protein is found in most bacteria and contributes to pathogenicity by promoting the formation of toxins and virulence factors. We will design specific inhibitors of DsbA by using a structure-based approach, implementing the leading edge technologies of fragment-based lead discovery by crystallography and NMR. We will then optimise the fragments to develop lead compounds and evaluate their suitability as DsbA inhibitors by in vitro and in vivo assays.Read moreRead less
The C-type Lectin, Mincle, Is A Macrophage Receptor For Candida Albicans.
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenge ....The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenger (phagocytic) cells, which are also important in determining the severity of the associated tissue lesions. A phagocytic cell that is central to both innate and adaptive immune responses is the macrophage, which not only takes up and kills the yeast, but also is capable of of killing and digesting it, and presenting the components to cells of the adaptive immune system. This project is based on the postulate that the outcome and severity of infection is determined, at least in part, by the early functional response of the macrophage to the overall virulence properties of the yeast. The response is initiated by interactions with cell-surface receptors, and this study will show that a novel macrophage receptor, Mincle, is an important part of the innate immune response to fungal infections. We have shown that it is associated with differences in susceptibility to yeast infections in inbred mouse strains; it can discriminate between different isolates of the yeast; and it initiates the inflammatory signalling cascade. Our project will define the specific role of this receptor in fungal infection. The results will be important in understanding the basic biology of host resistance, and will offer new opportunities for therapeutic intervention by selectively blocking or modifying different activation pathways.Read moreRead less
Elucidating the roles of steroid receptors in mitochondria. This project aims to elucidate the roles of newly discovered steroid receptors in the functions of mitochondria. The project will characterise their impact on cellular respiration, oxidative stress, and the induction of inflammation. By defining these processes in the healthy state and in response to common environmental challenges of infection and smoke exposure, the project will characterise the fundamental biology of entirely new pro ....Elucidating the roles of steroid receptors in mitochondria. This project aims to elucidate the roles of newly discovered steroid receptors in the functions of mitochondria. The project will characterise their impact on cellular respiration, oxidative stress, and the induction of inflammation. By defining these processes in the healthy state and in response to common environmental challenges of infection and smoke exposure, the project will characterise the fundamental biology of entirely new processes of how normal body hormones and administered steroids may function. This may eventually lead to new and more effective ways to control inflammation that will have significant benefits to mammalian health and improve health care and agriculture outcomes.Read moreRead less
Unravelling cell wall polysaccharide biosynthesis in pathogenic zygomycetes. This project aims to define mechanisms that control cell wall composition and stability in Rhizopus oryzae, a zygomycete fungus responsible for life-threatening human infections. The biochemical properties and function of vital enzymes involved in a newly discovered cell wall polysaccharide biosynthetic pathway will be determined using innovative approaches at the interface of biochemistry, microbiology, cell biology an ....Unravelling cell wall polysaccharide biosynthesis in pathogenic zygomycetes. This project aims to define mechanisms that control cell wall composition and stability in Rhizopus oryzae, a zygomycete fungus responsible for life-threatening human infections. The biochemical properties and function of vital enzymes involved in a newly discovered cell wall polysaccharide biosynthetic pathway will be determined using innovative approaches at the interface of biochemistry, microbiology, cell biology and structural biology. Expected outcomes include new knowledge on the enzymes that synthesise major fucose-based carbohydrates, to guide the future development of novel strategies for antifungal therapies. The data will also be applicable to animal protection from related zygomycete pathogens.
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Assembly Of Mitochondrial Respiratory Chain Complexes And Defects Associated With Disease
Funder
National Health and Medical Research Council
Funding Amount
$464,610.00
Summary
A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with ....A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a complicated procedure and we have little information on how its assembly is achieved. We do know however that mistakes in the assembly of these complexes (particularly Complex I) do happen. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others present later causing a range of degenerative diseases, particularly affecting brain, muscle and heart. Defects in the respiratory chain have also been implicated in Parkinson's disease, Alzheimer's disease, type-2 diabetes and in cell death. In order to understand how respiratory complex defects cause disease, we need to understand more about how these complexes are built. The aim of this proposal is to investigate how Complex I is assembled, how it interacts with other respiratory complexes, and to identify and characterise proteins that aid in its assembly. We will also analyse assembly defects in cells from patients with suspected respiratory complex deficiencies. This work will aid in our understanding of not only how protein complexes are built, but how defects in their assembly can cause disease. This will be informative to families of affected individuals and may aid in future diagnosis and prevention of diseases where defects in mitochondria are implicated.Read moreRead less
Novel human tryptases: their potential role in inflammatory diseases of the young and old. We have discovered a number of novel human tryptases, and while other members of this enzyme family have been implicated in the development of inflammatory diseases (including rheumatoid arthritis), little is known about these new molecules. We aim to characterise these new enzymes by determining what part of the body they are produced in, whether they are associated with specific inflammatory diseases, an ....Novel human tryptases: their potential role in inflammatory diseases of the young and old. We have discovered a number of novel human tryptases, and while other members of this enzyme family have been implicated in the development of inflammatory diseases (including rheumatoid arthritis), little is known about these new molecules. We aim to characterise these new enzymes by determining what part of the body they are produced in, whether they are associated with specific inflammatory diseases, and what target molecules they act on. A better understanding of these factors will increase the chances of finding cures and developing better treatments for important inflammatory diseases of the ageing population.Read moreRead less
Development and Characterization of Chemokine Receptor Mimics. The proposed research will provide important fundamental insights into the molecular events underlying inflammatory diseases and cancer metastasis. The innovative nature of the research and the significance of the results will enhance Australia's international research standing. Moreover, the insights gained from this work will contribute to the development of therapies that will ultimately enhance the quality of life for Australia ....Development and Characterization of Chemokine Receptor Mimics. The proposed research will provide important fundamental insights into the molecular events underlying inflammatory diseases and cancer metastasis. The innovative nature of the research and the significance of the results will enhance Australia's international research standing. Moreover, the insights gained from this work will contribute to the development of therapies that will ultimately enhance the quality of life for Australians.Read moreRead less