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.
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.
Cis Regulatory And Functional Analysis Of Genomic Loci With Implication In Hypothalamic Obesity Using The Zebrafish As A Model System
Funder
National Health and Medical Research Council
Funding Amount
$480,936.00
Summary
Gene regulatory mutations cause changes in gene activity (expression -level, -time, -site) and therefore decide about the availability of proteins. Regulatory mutations in uncharacterized genomic loci that are related to obesity and further their effects shall be identified, with emphasis on those affecting the hypothalamic food intake control circuits. Since the energy metabolism system and the obesity candidate genes are conserved, the model system zebrafish will be used for these analyses.
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.
Finding Therapeutic Targets For An Opportunistic Human Fungal Pathogen
Funder
National Health and Medical Research Council
Funding Amount
$404,068.00
Summary
Penicillium marneffei is a fungus that causes disease in patients with depressed immunity. This project models this infection in zebrafish, which have advantages for modelling infectious disease. It uses fluorescent fungi and fish with fluorescent immune cells to study the way white blood cells fight this infection, and mutant zebrafish and mutant fungi to find new therapeutic targets in the host-pathogen interaction.
Molecular And Cellular Basis For Muscle Regeneration In Zebrafish.
Funder
National Health and Medical Research Council
Funding Amount
$541,104.00
Summary
Muscle repair occurs via the use of muscle stem cells, which provide skeletal muscle with its regenerative capacity. Muscle stem cells are particularly important in muscle diseases such as muscular dystrophies where muscle regeneration is an important factor in disease progression. We will identify the processes controlling muscle regeneration utilising zebrafish as a model organism. We hope this research will lead to an understanding of how muscle stem cells are generated.
The Role Of Scube Genes In Hedgehog Signal Transduction
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this ....Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this pathway are mutated in the most common forms of human cancers. Understanding how this pathway is regulated is critical to designing strategies to treat the onset and progression of these cancers. The studies outlined in this grant plan to study a new component of this pathway that we have identified in our laboratory, in an easy to study vertebrate model, the zebrafish embryo. We plan to study how this class of proteins, termed scube proteins, acts to control activation of the pathway. We hope this will lead to a fuller understanding of this process, and at the same time help understand the nature of the end result of the patterning process within the muscle cells that we are studyingRead moreRead less