Identification And Characterization Of Substrates Of Tyrosine Kinases Involved In Hematopoiesis And Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these ge ....The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these genes have been identified in man and are likely to play a major role in the initiation and progression of distinct human malignancies. A significant number of proto-oncogenes are enzymes called protein tyrosine kinases (PTKs). Research has shown that the function of PTKs is to relay growth signals or other regulatory signals from the outer surface of the cell to specific target proteins inside the cell. These target proteins are needed to relay the signal to other target molecules and so on. This highly ordered process, involving a specific sequence of proteins, ensures that cells respond appropriately to a given signal. Our research focuses on identifying and studying the immediate targets of PTKs with the broad aim of understanding how PTKs control growth in normal and cancerous cells. We have recently developed a method that has enabled us to identify a new protein that may regulate the growth of blood cells. The research proposed here aims to extend our preliminary observations showing that the growth of specific types of blood cells is inhibited by this protein. We also plan to search for new targets of a PTK that is involved in leukemia. The findings of this research will provide important insight into how blood cells are regulated in health and disease.Read moreRead less
An Analysis Of The Lyn Tyrosine Kinase In The Regulation Of Hematopoiesis And Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$381,000.00
Summary
The Lyn kinase is an enzyme that is involved in relaying information across the cell membrane. It is a member of a family of genes that have been implicated in tumour development. Lyn is expressed in blood cells and it is involved in a variety of immunological responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn protein (Lyn-deficient mice) and one that expresses an activated f ....The Lyn kinase is an enzyme that is involved in relaying information across the cell membrane. It is a member of a family of genes that have been implicated in tumour development. Lyn is expressed in blood cells and it is involved in a variety of immunological responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn protein (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). Our previous studies have shown that Lyn-deficient mice have enhanced blood cell formation (hematopoiesis) and develop white blood cell tumours with age, whereas Lyn-up mice show no propensity to develop tumours. In this study we will examine in detail the role that Lyn plays in blood cell formation and tumourigenesis, and we will identify the pathways that underlie the phenotypes in Lyn-deficient mice. On completion of these studies we will have catalogued the molecules and pathways regulated by Lyn, and have an understanding of how Lyn functions in regulating development of specific populations of blood cells, and in suppressing or promoting tumour development.Read moreRead less
Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide ....Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide a short-cut to the cloning of one such gene. We have started with the mouse version, which is lost in leukemic cells. We have mapped the gene to within a very small chromosomal region, and we have identified a biological effect which correlates with loss of the gene. Our next step is to combine these two approaches to clone the gene. Because these genes are always highly conserved between species, we will be able to quickly clone the corresponding human gene, the loss of which is very likely to be important in cancer of various types.Read moreRead less
Molecular Analysis Of Myelodysplasia In The Nup98HoxD13 Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$351,502.00
Summary
Myelodysplastic syndrome is a preleukemic condition which is poorly understood and occuring at an increasing frequency. Unfortunately no targeted therapy exists. Two features of the disease are abnormal gene expression and abnormal cell death. We have a uniquely accurate model of this disease, and we plan to use it to investigate these two phenomena which will lead to greater understanding of the disease and new molecular targets for therapeutic agents to be developed and tested in our model.
Acute Lymphoblastic Leukemia And The Bone Marrow Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
This research aims to identify new drugs for the treatment of childhood and adult acute lymphoblastic leukemia (ALL). We have identified drugs that interfere with interactions between the bone marrow and leukemic cells and hypothesise that these will increase the potency of currently used chemotherapy. We will test these agents in animal models of human leukemia. By analysing the effects of these new drugs we will also understand how we can further improve treatments.
Transcriptional Complexes In Haematopoiesis And T-cell Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins LMO2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.