Inherited disorders of the blood, such as sickle-cell anaemia and thalassaemia, result from mutations in the genes that produce haemoglobin. Current treatments can partially alleviate some of the debilitating symptoms of these diseases but these treatments have significant side effects, and despite the best efforts of clinicians, many patients succumb to their conditions at an early age. It has been observed that certain individuals exhibit a milder form of the disease, as a consequence of the r ....Inherited disorders of the blood, such as sickle-cell anaemia and thalassaemia, result from mutations in the genes that produce haemoglobin. Current treatments can partially alleviate some of the debilitating symptoms of these diseases but these treatments have significant side effects, and despite the best efforts of clinicians, many patients succumb to their conditions at an early age. It has been observed that certain individuals exhibit a milder form of the disease, as a consequence of the reactivation of their foetal haemoglobin genes, (a distinct set of genes that would have been active in utero but are normally silenced around the time of birth). It is widely accepted that if pharmaceutical means can be found for reactivating the foetal haemoglobin genes then many patients would benefit. The regulation of the foetal globin genes, like most human genes, is complicated and there are few obvious means of increasing their activity. Nevertheless, it is believed that by investigating the molecular mechanisms by which they are controlled it will be possible to devise therapeutic agents that mimic these mechanisms or to develop agents that prevent the shutdown of the foetal genes around birth. To this end we have been working on the molecules that regulate the activity of the haemoglobin genes. We have recently cloned a number of DNA-binding proteins, and their co-factors, that appear to be involved in silencing foetal globin gene expression. This grant proposal is concerned with learning how these new molecules operate to silence gene expression as a first step towards designing agents that will prevent the silencing.Read moreRead less
In this grant we aim to study the moecular basis of cancer. The promoter regions of tumour suppressor genes are often modified in cancer by a chemical process called methylation. Methylation of DNA is associated with gene silencing. Therefore DNA methylation is commonly regarded as causing the silencing of genes in cancer. In this grant, we aim to determine if methylation is causal in triggering gene silencing in cancer, or if methylation is a consequence of gene silencing. This is a critical di ....In this grant we aim to study the moecular basis of cancer. The promoter regions of tumour suppressor genes are often modified in cancer by a chemical process called methylation. Methylation of DNA is associated with gene silencing. Therefore DNA methylation is commonly regarded as causing the silencing of genes in cancer. In this grant, we aim to determine if methylation is causal in triggering gene silencing in cancer, or if methylation is a consequence of gene silencing. This is a critical distinction in understanding the role of methylation in cancer development.Read moreRead less
Epigenetic Inheritance Through Meiosis At The Agouti Locus In Mice
Funder
National Health and Medical Research Council
Funding Amount
$182,699.00
Summary
The manifestations of many genetic traits do not conform to the rules of Mendelian inheritance. In humans, some alleles give a completely predictable phenotype, while others display a wide range of phenotypes, described as differences in penetrance and expressivity. As the phenotype associated with a particular gene in humans may be modified by the genotype at unlinked modifying loci and by environmental factors, it is difficult to determine to what extent any single factor is responsible for va ....The manifestations of many genetic traits do not conform to the rules of Mendelian inheritance. In humans, some alleles give a completely predictable phenotype, while others display a wide range of phenotypes, described as differences in penetrance and expressivity. As the phenotype associated with a particular gene in humans may be modified by the genotype at unlinked modifying loci and by environmental factors, it is difficult to determine to what extent any single factor is responsible for variability. In mice, however, a number of examples of variable expressivity have been reported in conditions where genetic background and environment have been controlled. For example, the phenotypes of mice with mutations at the agouti locus can vary substantially between genotypically identical littermates. Epigenetic modifications such as DNA methylation are known to be involved. Furthermore, the phenotypes of the offspring are related to the phenotype of the mother and recent experiments carried out in our laboratory suggest that this is the result of inheritance of the epigenetic state of the allele through the female germline. This is the first report of epigenetic inheritance at an endogenous gene in mammals. The experiments described in this project should help to clarify the mechanisms involved in variable expressivity and epigenetic inheritance. Variable expressivity in combination with epigenetic inheritance may be viewed as an alternative method of inheritance of genetic traits which does not involve DNA mutation, but which can be carried from generation to generation in a semipermanent way. Understanding the mechanisms underlying these phenomena is a challenge for contemporary genetics.Read moreRead less
Analysis Of Very Early Cancer-related Methylation Abnomalities
Funder
National Health and Medical Research Council
Funding Amount
$422,310.00
Summary
The factors that are involved in triggering cancer are still unknown. Increasing evidence however indicates that the DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called tumour suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by a process called DNA methylation. We have found that an important tumour suppressor gene called p16 is inactivated and chemically methylated in breast epithelial cells at the st ....The factors that are involved in triggering cancer are still unknown. Increasing evidence however indicates that the DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called tumour suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by a process called DNA methylation. We have found that an important tumour suppressor gene called p16 is inactivated and chemically methylated in breast epithelial cells at the stage when the cell changes to a pre-cancer cell. This grant is aimed at finding what triggers the silencing and methylation of the p16 gene in this early pre-cancer stage. We also plan to identify other genes are methylated and undergo inactivation the pre-cancer breast cells. These results will have an impact on understanding the molecular mechanism that makes a breast cell susceptible to cancer and may lead to insights into new prevention and treatment strategies.Read moreRead less
Oxidative Damage and Cell Ageing. This research will benefit Australia by providing a fundamental understanding of how cells age. This will have immediate international impact at the scientific level and will inform strategies to reduce the rate of ageing and alleviation of age-related disorders. In the longer term the research may provide commercial and social outcomes by identifying antioxidant systems that will provide a genuine benefit in reducing ageing.
Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems ar ....Cellular Responses to Oxidative Damage: Cell Aging. The aim of this project is to identify the mechanisms by which oxidative stress and free radical damage cause cell aging. This work will make a significant contribution to our understanding of the aging process in cells by identifying the major reactive oxygen species that contribute to cell aging, which defence systems and antioxidants provide the greatest degree of protection, what damage accumulates as cells age and which genetic systems are activated as during the process.Read moreRead less
CesA (cellulose synthase) genes of Arabidopsis; all doing the same job or specialists cooperating to make the most abundant biopolymer. The biosphere makes more cellulose than any other polymer with fibre industries depending on its physical properties and atmospheric carbon dioxide levels depending on its stability as a carbon sink. Demonstrations that cellulose production needs CesA genes drove recent progress in elucidating the mechanism of synthesis. CesA proteins all look very similar but i ....CesA (cellulose synthase) genes of Arabidopsis; all doing the same job or specialists cooperating to make the most abundant biopolymer. The biosphere makes more cellulose than any other polymer with fibre industries depending on its physical properties and atmospheric carbon dioxide levels depending on its stability as a carbon sink. Demonstrations that cellulose production needs CesA genes drove recent progress in elucidating the mechanism of synthesis. CesA proteins all look very similar but if all do the same job, why do plants need so many and why do none seem redundant? We will make gene interchanges in transgenic plants, build chimeric genes and identify where each CesA protein operates. This will identify their individual and cooperative contributions to cellulose production.Read moreRead less
Function of a new splicing factor, RBM4. New genomic knowledge is revolutionizing our world. However our understanding of the basic mechanisms of RNA maturation, especially regulation of splicing lags significantly behind our understanding of related genomic processes. This project is a genetic approach to help elucidate the function of new splicing factors and characterize the way in which specific RNA sequences are recognized. It should promote the better understanding of regulatory events inv ....Function of a new splicing factor, RBM4. New genomic knowledge is revolutionizing our world. However our understanding of the basic mechanisms of RNA maturation, especially regulation of splicing lags significantly behind our understanding of related genomic processes. This project is a genetic approach to help elucidate the function of new splicing factors and characterize the way in which specific RNA sequences are recognized. It should promote the better understanding of regulatory events involved in controlling gene expression during development and differentiation. Results from this project will also provide new insights into the 'multifunctionality' of cellular proteins and will illustrate the importance of RNA studies in molecular medicine.Read moreRead less