MicroRNA Pathway Control Of Immune Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$631,370.00
Summary
The immune system is comprised of many different cell types, each with a specialised function. Many are short-lived and must be continually replenished throughout life. Abnormalities in this process underlie many human diseases, including immunodeficiency, autoimmunity and cancer. My laboratory seeks to understand the molecular pathways that control development of immune cells and to identify the defects that lead to disease.
Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioi ....Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioinformatics to dissect the functions of the lymphoid stromal cells and their roles in the swelling of lymphoid tissues during immune responses. This will provide vital information about the biology of these understudied cells and reveal the ways in which they support the generation of immunity.Read moreRead less
Mechanisms connecting diet, metabolism, gut microbiota and immunity. This project will identify the role of short chain fatty acids and the G-protein coupled receptor (GPR43) in regulating immune responses. This could explain how diet affects immune responses and also how certain bacteria in the gut provide benefits for immune defence.
Blimp-1: A Master Regulator Of B-lymphocyte Terminal Differentiation?
Funder
National Health and Medical Research Council
Funding Amount
$154,250.00
Summary
B lymphocytes are the antibody-producing cells of the immune system. They are formed in the bone marrow, and are exported to the body to circulate, searching for signs of infection. These circulating cells are not fully mature, but when they encounter an invader, with the help of other immune cells, they change. Most become antibody-producing cells, the final, operational cells of the B cell lineage. A few cells are set aside as memory cells that can rapidly become antibody-producing cells shoul ....B lymphocytes are the antibody-producing cells of the immune system. They are formed in the bone marrow, and are exported to the body to circulate, searching for signs of infection. These circulating cells are not fully mature, but when they encounter an invader, with the help of other immune cells, they change. Most become antibody-producing cells, the final, operational cells of the B cell lineage. A few cells are set aside as memory cells that can rapidly become antibody-producing cells should the same infection occur again. This is the basis of vaccination. The secretion of antibodies into the serum (that can bind to and eliminate an invader anywhere in the body) is the main function of B lymphocytes. This project will study the genes that allow B cells to become antibody-secreting cells (called ASC). We will focus on the gene for Blimp-1, the B lymphocyte-induced maturation protein, which has been called the master regulator of ASC formation. This claim is based largely on circumstantial evidence, and has not been directly tested genetically. We have made a mouse in which the Blimp-1 gene has been altered so that we can disable it in carefully controlled way. Using this knockout mouse, we can directly test the requirement for Blimp-1 in ASC and in other cell types. We will study these animals, using many tests that can accurately measure the behaviour of isolated cells, or the immune responses of the animals. We will examine other genes that are thought to be required for ASC to form or to perform their work, to see if loss of Blimp-1 (a known gene silencer) has impacted on these other genes. In this way, we expect to identify the genetic program that drives a B cell to become a mature ASC. Using this knowledge, we hope eventually to be able to study diseases of ASC in humans (as occur in allergy, asthma, rheumatoid arthritis and leukaemia). This information may also be used to improve the outcome of vaccination.Read moreRead less
Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contr ....Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contribute to the development of new generation vaccines and therapies to protect against tissue-specific infectious diseases, cancers and autoimmune diseases.Read moreRead less
Understanding the life and death of Mucosal-associated invariant T cells. Cell death of naïve T cells in lymphoid organs is well-understood. However, T cells only gain their function upon activation, and how activated T cells regulate their life or death remains unclear. Mucosal-associated Invariant T (MAIT) cells are abundant in non-lymphoid tissues as key local players in immunity, and share some features of activated conventional T cells. This project aims to define how MAIT cell survival and ....Understanding the life and death of Mucosal-associated invariant T cells. Cell death of naïve T cells in lymphoid organs is well-understood. However, T cells only gain their function upon activation, and how activated T cells regulate their life or death remains unclear. Mucosal-associated Invariant T (MAIT) cells are abundant in non-lymphoid tissues as key local players in immunity, and share some features of activated conventional T cells. This project aims to define how MAIT cell survival and death are controlled. It combines methods we developed to track MAIT cells in vivo with expertise in cell death analysis. This project is expected to elucidate the complex mechanisms controlling MAIT cell survival/death and increase our fundamental understanding of cell death mechanisms of activated T cells.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE220100830
Funder
Australian Research Council
Funding Amount
$464,928.00
Summary
Elucidating the genesis of MAIT cell-mediated immunity. T cells develop in the thymus and proceed to survey our body probing molecules that signal if anything is abnormal. A specialised subset of T cells, mucosal associated invariant T (MAIT) cells are crucial in detecting microbial molecules and infection, yet their numbers vary widely between individuals. A key problem is that the factors controlling their development and function are poorly understood. This proposal aims to decode this critic ....Elucidating the genesis of MAIT cell-mediated immunity. T cells develop in the thymus and proceed to survey our body probing molecules that signal if anything is abnormal. A specialised subset of T cells, mucosal associated invariant T (MAIT) cells are crucial in detecting microbial molecules and infection, yet their numbers vary widely between individuals. A key problem is that the factors controlling their development and function are poorly understood. This proposal aims to decode this critical issue in MAIT cell biology, using innovative tools to investigate the molecular basis underpinning their development in the thymus. This work will provide vital, fundamental discoveries into how MAIT cells are produced and regulated, as we ultimately wish to harness MAIT cells to improve human health. Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100001
Funder
Australian Research Council
Funding Amount
$875,000.00
Summary
A 3-photon imaging system for deep live imaging. This project aims to establish Australia’s first 3-photon microscope system with adaptive optics for deep intravital imaging. This advanced imaging system will enable researchers to investigate the biology of cells and tissue structures in a wide range of organs and engineered tissues, to a degree not possible with existing technology. This project will capitalise on advanced laser, microscope and adaptive optics technologies with the expected out ....A 3-photon imaging system for deep live imaging. This project aims to establish Australia’s first 3-photon microscope system with adaptive optics for deep intravital imaging. This advanced imaging system will enable researchers to investigate the biology of cells and tissue structures in a wide range of organs and engineered tissues, to a degree not possible with existing technology. This project will capitalise on advanced laser, microscope and adaptive optics technologies with the expected outcomes to include the generation of new knowledge of major biological systems, including the immune system and the nervous system. This will provide significant benefits to fundamental interdisciplinary research into immunology, infectious disease, neuroscience, mechanobiology and engineering.Read moreRead less
Discovery Of Novel T Cell Oncogenes By Using A Functional Retroviral CDNA Library Screen.
Funder
National Health and Medical Research Council
Funding Amount
$692,470.00
Summary
T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is ....T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is crippled. Patients generally die due to opportunistic infection. The molecular causes of T cell leukaemia are slowly being discovered. Up to 50% of all human T cell leukaemias overexpress SCL-TAL-1. Other T cell leukaemia-causing genes (oncogenes) include Ras and Notch. Current leukaemia treatments include chemotherapy and bone marrow transplants but even these fail ~30% of the time. Consequently, all T cell oncogenes need to be discovered so that disease-specific treatments can be generated. This proposal will utlise a functional retroviral cDNA library screen to uncover novel T cell lineage commitment genes and T cell oncogenes. This will be accomplished by constructing a coloured [GFP] cDNA library (a library of genes) that will be transfected (inserted) into immature T cells that cannot develop down the T cell pathway owing to the lack of a crucial gene (Rag-1). The T cell oncogene Ras and the T cell lineage commitment gene Notch can move cells past the Rag-1 block. If there is a gene in the cDNA library that can compensate for the lack of Rag-1 and allow the cells to mature we will detect it using high speed flow cytometryic cell sorting (like sieving weevils from flour very quickly). Once we find this cell we will isolate the gene using the colour tag. The potential oncogenes uncovered will provide the foundation for next generation drug development that targets each leukaemia based on its cause.Read moreRead less
New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based intervent ....New guardians of the mucosa: Molecular characterisation of M cell biology. We aim to completely define the cellular and molecular biology of gut and lung M cells for the first time. We will elucidate how they develop, are regulated and function at a molecular level, and how M cells maintain normal gut and lung tissues and induce immune responses to protect against microbial challenges. In the future, the new insights will be essential pre-requisites for the development of mucosal-based interventions and vaccines that protect the gut and lung from infectious and inflammatory issues. The harnessing of effective immune responses to control such challenges, are of enormous fundamental and long-standing biological interest, and are amongst the most important areas of current scientific research.Read moreRead less