THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. We have identified a number of genes that act to negatively regulate the cell cycle, 2 of which have characteristics typical of tumour suppressors. We have identified candidate genes for 3 of these mutations, all of which encode novel proteins related to mammalian proteins involved in negative regulation of cell proliferation or tumour suppressors. In this proposal we seek to determine the way in which these proteins function to control cell proliferation in Drosophila. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is likely to be highly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
THE ROLE OF A NOVEL NEGATIVE CELL CYCLE REGULATORY PATHWAY DURING ANIMAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. This proposal focuses on one of these regulators, Phyl, and the proteins that function with it, Sina and Ebi, which act to target and lead to the degradation of key proteins that negatively regulate differentiation and that promote cell proliferation. In this proposal we seek to understand how the Ebi-Phyl-SIna protein complex functions to control cell proliferation in Drosophila. In addition, we will examine whether the Sina complex also acts to inhibit cell proliferation in the mouse. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Analysis Of The Scrib, Dlg And Lgl Tumour Suppressors In Cell Cycle Regulation Using The Drosophila Animal Model System
Funder
National Health and Medical Research Council
Funding Amount
$476,500.00
Summary
Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in th ....Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal focuses on a group of these regulators, the Drosophila tumour suppressors, Scrib, Dlg and Lgl, which act in a common genetic pathway to link cell polarity (cell shape) to cell proliferation. In mutants of these genes, cyclin E is up-regulated and inappropriate cell proliferation occurs. The aims of this proposal are to determine the signalling pathway and the transcription factors that act to upregulate cyclin E in scrib-dlg-lgl mutants. We will use the powerful genetics of Drosophila to examine candidate genes and to screen for novel genes involved in the upregulation of cyclin E in scrib-dlg-lgl mutants. The expected outcome of this project is to elucidate how Scrib-Dlg-Lgl act to control cell proliferation. scrib, dlg and lgl are present in mammals, therefore, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Body Segment Identity Specification By The Transcription Regulator, Moz
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood ....One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood stem cells. Moz can regulate the activity of genes, but which genes it regulates in vivo is unknown. In the absence of Moz, mice are born with a cleft palate, lack the thymus, where immune cells are instructed, and fail to form the lung blood circulation, so that they are unable to supply their blood with oxygen after birth. Moz deficiency also causes defects of the vertebrate column, such that individual vertebrae acquire the appearance of their neighbours. These symptoms are typical for a general defect in positional information of individual body segments with respect to their location along the body axis. We will investigate the molecular mechanisms that require Moz in patterning of the body axis. This project will characterize a genetic mechanism that is crucial for normal development of the palate, the aorta and the vertebrate column.Read moreRead less
The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
Genetic Control Of Body Patterning: Intersection Of Transcriptional And Signalling Activity In Head Formation
Funder
National Health and Medical Research Council
Funding Amount
$579,932.00
Summary
A most critical step in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. The objective of our research is to understand how the mechanisms that control genetic activity and cell-to-cell signalling may cooperate in the formation of the head and face of the embryo. The outcome will focus future clinical investigations to the most relevant genetic determinants of craniofacial defects.
Temporal And Spatial Regulation Of Caspases In Development And Metamorphosis
Funder
National Health and Medical Research Council
Funding Amount
$369,072.00
Summary
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in g ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in general to maintain the correct number of cells in the body. As such, dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. Various molecules that are involved in the execution and regulation of apoptosis are potentially excellent targets for therapeutic intervention in a number of disorders and will lead to the development of novel drugs for the treatment and prevention of many pathological conditions. In the present proposal, we aim to study what type of caspases are involved in sculpting of various organs and tissues during development.Read moreRead less
The Identification Of Genes Involved In Mammalian Craniofacial Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Birth defects arising from abnormal development of the embryo are a major cause of infant mortality and childhood disabilities. On average 3-4% of liveborn babies have a major congenital abnormality, and of the 15-20% of pregnancies which spontaneously abort, many are due to chromosomal or other developmental anomalies. A common feature of many developmental disorders is dysmorphology of the face, suggesting that genes important in patterning the face are also important in the development of oth ....Birth defects arising from abnormal development of the embryo are a major cause of infant mortality and childhood disabilities. On average 3-4% of liveborn babies have a major congenital abnormality, and of the 15-20% of pregnancies which spontaneously abort, many are due to chromosomal or other developmental anomalies. A common feature of many developmental disorders is dysmorphology of the face, suggesting that genes important in patterning the face are also important in the development of other organ systems. During development of the embryo many of the features of the face derive from a series of swellings termed the pharyngeal arches. The complex processes which determine how the face develops are in a large part controlled by the co-ordinated expression of a large number of genes in the first two of the five pharyngeal arch pairs. While we know some of the genes involved in these processes, the precise mechanisms of craniofacial development are relatively poorly understood. In this project we propose a large scale approach to identifying genes involved in development of the mammalian face and to further delineating their role in development and human disease. This approach takes advantage of state of the art genomic technologies available at the IMB and through existing collaborations overseas. In collaboration with Dr Bento Soares (University of Iowa) we have constructed a library containing all of the genes which are expressed in the first two pairs of pharyngeal arches in the developing mouse embryo. Using an approach designed to eliminate all those genes which are expressed in all or most tissues of the body and play a general role in the body's metabolism, we will select for those genes which play a specific and important role in embryonic development. We will then isolate the human counterparts of these genes and more thoroughly investigate their role in embryonic development and disease.Read moreRead less
The Role Of The HuB RNA-binding Protein In Post-transcriptional Gene Regulation In The Pre-gastrula Zebrafish Embryo
Funder
National Health and Medical Research Council
Funding Amount
$545,216.00
Summary
The precise control of protein expression is absolutely critical in biology. The key decisions about which genes are turned on or off at any one moment control the proper growth of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. The spatio-temporal control of genes is critcal during embryogenesis and we aim to understand how these processes underlie development in the vertebrate embryo.
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