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
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
Understanding The Multistep Pathogenesis Of T-cell Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$701,992.00
Summary
Lmo2 is a transcription factor whose overexpression is a common cause of T-cell leukaemia. This project seeks to identify downstream targets of Lmo2 that cause T-cell leukemia. In addition, the origins and effects of secondary mutations that collaborate with Lmo2 in causing T-cell leukaemia will be determined. This will improve our understanding of how T-cell leukaemia develops and provide new molecular targets for therapy.
Structure And Composition Of The Pre-T Cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
In order to recognize a wide variety of pathogens, humans produce many different T cell receptors (TCRs) by the process of gene-rearrangement. However, gene-rearrangement may not always lead to a functioning TCR. We are studying the pre-TCR protein that is responsible for monitoring the success of gene-rearrangement and is thus essential for the formation of a robust immune system. Understanding pre-TCR function will lead to new treatments for immune related diseases.
Cell Therapy For The Prevention And Treatment Of Invasive Filamentous Fungal Infections In Patients With Haematological Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$987,873.00
Summary
Common fungi in the environment do not cause disease in healthy individuals. They are however responsible for fatal infections leading to death when the immune system is impaired following treatment for blood cancers. This project aims to restore defects in the immune system of these patients by giving them cells that have been grown to recognize and kill fungus.
Regulation Of A Novel Target Gene, Aldehyde Dehydrogenase 1, By HOX11 In Childhood Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$382,027.00
Summary
Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is th ....Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is therefore essential in order to understand the mechanisms by which TF oncogenes induce tumour growth. However, very few target genes of TF's implicated in T-ALL have been discovered. HOX11 is one example of a TF aberrently expressed in childhood T-ALL. Recently we have shown that a gene called ALDH1 is under the control of HOX11 in a model cell system and also during normal development. The proper control of ALDH1 expression is important to the cell because it functions in the conversion of vitamin A to retinoic acid, a signalling molecule that critically affects cell growth and development. A related gene called RALDH2, that is also involved in retinoic acid synthesis, has very recently been shown to be under the control of other TF's implicated in T-ALL. These two discoveries therefore suggest that this disease may occur via a common pathway involving altered retinoic acid signalling. This project seeks to find out whether ALDH1 is also a target of HOX11 in T-ALL and if so, what effects it has on the cell. It also aims to determine how HOX11 influences the expression of ALDH1 and whether there are any other genes controlled by HOX11 that may be involved in tumour development. HOX11 provides an ideal model system to study the events leading to cancer that occur as a result of abnormal control of gene expression. Ultimately, such studies may lead to a better understanding of our normal biology as well as provide the basis for the design of improved cancer therapies.Read moreRead less
Asymmetric Cell Divison In T Cell Development: Consequences For Immunity And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$642,608.00
Summary
Human health depends upon the development of an immune system that can effectively control infection without damaging normal tissue. In this project, we assess a new paradigm by which immune cell development might be controlled, in which an immune cell precursor divides in such a way that its two daughters inherit different molecular constitutents that subsequently regulate the adoption of different cell fate. The likely consequences of this phenomonon on immunity and cancer will be explored.
Regulation Of T Cell Effector Function In Peripheral Tissues
Funder
National Health and Medical Research Council
Funding Amount
$698,550.00
Summary
Protection from infections relies on different types of immune cells. While some of these cells are found in the blood, others reside in peripheral tissues such as the skin. We will analyse the function of these peripheral immune cells to understand how they work to fight off infections. We will also investigate how so-called memory cells that permanently reside in peripheral tissues can protect from re-infection with similar bacteria or viruses.
Modulation Of Cytokine Responses To Improve Transplant Outcome.
Funder
National Health and Medical Research Council
Funding Amount
$26,186.00
Summary
Bone marrow transplantation remains a mainstay of curative therapy for haematological malignancies. This curative effect is mediated by the transplanted donor immune system which rejects the recipient malignancy. However, the procedure is limited by its serious side effect, known as graft-versus-host disease. This application seeks to better understand these two processes at both an immunological and clinical level with the aim of separating the two so that more patients may be cured of leukaemi ....Bone marrow transplantation remains a mainstay of curative therapy for haematological malignancies. This curative effect is mediated by the transplanted donor immune system which rejects the recipient malignancy. However, the procedure is limited by its serious side effect, known as graft-versus-host disease. This application seeks to better understand these two processes at both an immunological and clinical level with the aim of separating the two so that more patients may be cured of leukaemia.Read moreRead less
Identifying The Ontogeny And Fate Of T Follicular Helper Cells By Two-photon Photoconversion
Funder
National Health and Medical Research Council
Funding Amount
$623,070.00
Summary
The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vacc ....The aim of this proposal is to investigate immune cells called T follicular helper cells using a novel microscopy-based method that we have developed. This method lets us ‘tag’ these cells in a way that enables us to distinguish them from all other cells and follow them as they migrate to different immunological compartments during the response. T follicular helper cells are important for protective immune responses against pathogens and a better understanding of this T cell subset will aid vaccine design.Read moreRead less