A New BTB-ZF Family Transcription Factor Required In Development And Dysregulated In Malignant Disease
Funder
National Health and Medical Research Council
Funding Amount
$439,813.00
Summary
We are studying the function and biology of a novel gene that looks like a generegulator. We generated a zebrafish mutant with defective myeloid development, and we found this gene causes the defect. This mutant fish provides a handle on the biological function of the gene in development. This gene has the hallmarks of a transcription factor and we will study how it regulates other genes, and how it may be a target for treatment of several cancers in which expression of this gene is activated.
Identification Of Genes Important In Myeloid And Haemopoietic Development By Genetic Screening In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized ....Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish strains exist in which red blood cell development is perturbed - this was easily recognized because the transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that specifically affect white blood cell development in a process called genetic screening. Fish with different sets of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell development. We have tested our approach and identified several mutants affecting white blood cell development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white blood cell growth and development. The fish themselves will provide insights into the causes of congenital diseases of white blood cells. Since many genes involved in early development are also important in cancer, we believe that newly identified genes will also help understand the causes of abnormal growth of white blood cells in leukaemia.Read moreRead less
Studies Of Myeloid Leukaemogenesis In The Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$171,827.00
Summary
This project aims to investigate the causes of white blood cell cancer, or leukaemia, at the molecular level, using a novel approach in zebrafish. Zebrafish provide a powerful experimental model for developmental genetics, largely due to the visual and technical accessibility of embryos for experimentation. We plan to introduce a fluorescent molecular tag into the white blood cells in order to directly visualise them. We will then predispose these fish to leukaemia and screen for mutants with en ....This project aims to investigate the causes of white blood cell cancer, or leukaemia, at the molecular level, using a novel approach in zebrafish. Zebrafish provide a powerful experimental model for developmental genetics, largely due to the visual and technical accessibility of embryos for experimentation. We plan to introduce a fluorescent molecular tag into the white blood cells in order to directly visualise them. We will then predispose these fish to leukaemia and screen for mutants with enhanced or suppressed leukaemia. We anticipate that the mutants will allow new genes involved in the development of leukaemia to be identified.Read moreRead less
Determining The Pathobiology Of Human Sarcomeric Myopathies Using Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$509,541.00
Summary
Laing muscular dystrophy and ACTA1 congenital muscular dystrophy are severe muscle diseases with high morbidity. We will create zebrafish strains that carry these diseases and use these to understand the causes of muscle failure and investigate possible areas of treatment for these conditions.
Bcl-2 Proteins And The Regulation Of The Megakaryocyte Lineage.
Funder
National Health and Medical Research Council
Funding Amount
$416,240.00
Summary
Platelets are tiny cells that circulate in the blood. They are essential for blood clotting. Too few platelets leads to uncontrolled bleeding. Platelets are produced in the bone marrow by cells called 'megakaryocytes'. Cancer chemotherapy often causes dangerous decreases in platelet count - this is thought to be because it kills megakaryocytes. We will pinpoint the molecules responsible for megakaryocyte life and death. This has the potential to make the side effects of chemotherapy less severe.
Analysis Of The Function Of The Presenilin Genes During Embryogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$197,317.00
Summary
The presenilin genes are essential for normal human mental health. Deleterious changes in presenilin genes are the root cause of 60% of Alzheimers Disease that is inherited within families (ie. Oearly onsetO Alzheimers disease) and of 10% of all Alzheimers disease. Normal presenilin genes are also necessary for correct embryo development. There is evidence that the proteins produced by the presenilin genes interact with other proteins such as those produced by the Notch genes. Changes in Notch g ....The presenilin genes are essential for normal human mental health. Deleterious changes in presenilin genes are the root cause of 60% of Alzheimers Disease that is inherited within families (ie. Oearly onsetO Alzheimers disease) and of 10% of all Alzheimers disease. Normal presenilin genes are also necessary for correct embryo development. There is evidence that the proteins produced by the presenilin genes interact with other proteins such as those produced by the Notch genes. Changes in Notch genes can also produce dementia and developmental defects. However, despite their obvious importance, we know little about how presenilin and Notch genes function and interact! We want to understand how presenilin genes interact with Notch genes and any other genes that are important for normal embryo development. To investigate this we are using the eggs of a small, freshwater fish, the zebrafish. These eggs are easily available (hundreds are produced by a female zebrafish every week), accessible and, being transparent, every cell in a developing zebrafish egg can be observed! They also develop about one hundred times faster that a human! In our experiments we will produce antibodies to the protein products of the presenilin and Notch genes of zebrafish and then use these to observe interactions between the presenilin and Notch proteins. We will observe how changes in the levels of presenilin protein in an embryo affect the function of the Notch genes and we will attempt to discover other genes that are affected by such changes. This work will be important for understanding how genes interact to create our bodies during embryo development. Also, since genes typically interact in similar ways during embryo development and in adults, the discoveries that we make will help us to understand what goes wrong when changes in the presenilin genes cause Alzheimers disease.Read moreRead less
Characterisation Of Conserved Sox18-dependent Genes In Lymphatic Vascular Development
Funder
National Health and Medical Research Council
Funding Amount
$401,355.00
Summary
Lymphatic vessels are important in a number of diseases including lymphoedema and cancer. There is a significant gap in our basic understanding of how lymphatic vessels form. We have identified a series of genes that are regulated downstream of the lymphatic master gene Sox18 in mouse lymphatic vessels. This study aims to characterise these genes using complementary model systems. The genes and pathways identified will represent potential therapeutic targets in a number of disease contexts.
The Mechanism Of Ccbe1 Function During Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$502,437.00
Summary
Tumours induce the regional growth of lymphatic vessels (in a process termed lymphangiogenesis) and then spread (a process termed metastasis) via lymphatic vessels and lymph nodes. Inhibiting lymphangiogenesis can inhibit metastasis. We have identified a gene called ccbe1 that is essential for lymphangiogenesis during development. We aim to understand how this potential therapeutic target functions at the molecular level during lymphangiogenesis.