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
The Function Of Transcription Factor SCL In T Cell Development.
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double- ....SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double-edged approach will allow us to monitor the effects of SCL on maturing T cells with a precision that has never previously been achieved. Results from this approach will provide new insights into how T cell leukaemia develops and provide the foundation for new rational based treatments.Read moreRead less
CD4+ T Cell-independent Immunity Against Salmonellae
Funder
National Health and Medical Research Council
Funding Amount
$550,226.00
Summary
Salmonella typhimurium is an important pathogen in both developed and developing countries where it causes significant HIV-linked morbidity. There is a pressing need to understand how immunity might be established against this organism that will function when the patient is immunocompromised either through age or through a comorbidity like HIV.
Immunoregulation In The Pathogenesis And Therapy Of Autoimmune Anti Myeloperoxidase Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$283,880.00
Summary
Glomerulonephritis (GN) is a major health burden and crescentic GN is the most severe form. Most patients have autoantibodies to their own white blood cell ANCA, causing the disease. This study will use a mouse model of ANCA associated autoimmunity causing crescentic GN to define the normal mechanisms preventing the development of this disease (immunoregulation) and test the potential of new cell based therapies to prevent and treat the disease.
Mechanisms Of Disease In Humans With MPO-ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Glomerulonephritis (GN) is a major health burden and crescentic GN is the most severe form. Most patients have autoantibodies to their own white blood cell ANCA, causing the disease. This study plans to assess immune cells and kidney biopsies from patients with anti-MPO GN to define more precisely the immune mechanisms causing disease.
Role Of Dendritic Cell Subsets In The Generation Of CD4 T Cell Memory
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
This project studies the mechanisms responsible for establishing immunologic memory that is generated by vaccination and determines its efficacy. We aim to identify and study previously unacknowledged factors that critically affect the efficacy of vaccination. The results will be significant for both preventative and therapeutic vaccination (cancer, autoimmunity) and will help us to design new vaccines to improve immune function in infection, autoimmunity and cancer.