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
The Role Of The Microphthalmia Transcription Factor Family In Macrophage Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$367,193.00
Summary
Macrophages are large white blood cells that are also found in all the tissues of the body. They are a major part of the front line defence against infection and malignancy, but they also cause much of the pathology of many diseases particularly those in which there is chronic inflammation. Macrophages, like all the cells of the blood, are produced from the bone marrow. In the process of macrophage production a suite of genes must be switched on so that the mature macrophage can carry out its fu ....Macrophages are large white blood cells that are also found in all the tissues of the body. They are a major part of the front line defence against infection and malignancy, but they also cause much of the pathology of many diseases particularly those in which there is chronic inflammation. Macrophages, like all the cells of the blood, are produced from the bone marrow. In the process of macrophage production a suite of genes must be switched on so that the mature macrophage can carry out its functions. This project aims to understand the process of selective gene expression in macrophages. It is based upon the identification of four members of a gene family, called the microphthalmia gene family, as candidate master genes that control the overall process of macrophage production. We seek to understand how the products of genes interact.Read moreRead less
Functional Characterisation Of Regulators Of Human Globin Gene Switching
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
Red blood cells produce haemoglobin, a tetramer of two alpha globin chains and two beta-globin chains. Haemoglobin reversibly interacts with oxygen in such a way that it efficiently shuttles oxygen between the lungs and the rest of the body. Integrity of the hemoglobin molecule, and red cells which carry it, is essential for life of all organisms with blood. The alpha-globin and beta-globin chains that make up haemoglobin are prodcued by red cell precursors in the bone marrow according to the ge ....Red blood cells produce haemoglobin, a tetramer of two alpha globin chains and two beta-globin chains. Haemoglobin reversibly interacts with oxygen in such a way that it efficiently shuttles oxygen between the lungs and the rest of the body. Integrity of the hemoglobin molecule, and red cells which carry it, is essential for life of all organisms with blood. The alpha-globin and beta-globin chains that make up haemoglobin are prodcued by red cell precursors in the bone marrow according to the genetic blueprint (genes) that are inherited. Genetic disorders resulting from defects in the beta-globin gene are the most common inherited disorders of man. Children who fail to make beta-globin have a disease known as beta-thalassaemia. They are transfusion dependent from ~ 6 months of age and need intensive chelation therapy (infusions) to avoid the serious consequnces of iron overload. The average life expectancy in Western cultures is ~ 30 years. There is no cure. In third world countries where a reliable blood supply is unavailable, death occurs earlier. Patients are aften infected with blood born viruses such as hepatitis B, hepatitis C and the AIDS virus, HIV. Sickle cell anaemia is also a very common disease. It is due to a single DNA base mutation at in the beta-globin gene that results in production of normal amounts of a defective beta-globin molecule (HbS). In low oxygen, HbS molecules polymerize in red cells and irreversibly damage them. These red cells get trapped in small blood capillaries throughout the circulation causing small infarcts which results in severe pain and organ damage. The life expectancy is <2 years in the thrid world and ~20-30 years in the west. The irony of these two diseases is that there is a perfectly normal fetal globin gene that has been silenced during fetal life. This grant aims to understand the mechanism of the switch from fetal to adult globin gene usage so it can be reversed in adults with b-thalassemia and sickle cell diseaseRead moreRead less
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
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
Regulation Of Adult Colonic Crypt Homeostasis And Activation Of Colon Cancer Metastasis Genes By C-Myb
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number ....Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number of cells needed to have a healthy blood system are similar if not identical to the rules used by the colon. This is because the colon also produces a massive number of cells each with special tasks and a defined life span of a few days. It is this rapid expansion of cell numbers and the programmed short life span of cells that necessitates multiple controls and very tight regulation. Furthermore if this process is hijacked by genetic changes that undermine these controls then there are numerous opportunities to initiate and potentiate malignant change or cancer. This project examines the role of the same genes in two contexts. Firstly when the genes are expressed at normal, highly regulated levels associated with the normal biology of the colon. The second context is when these genes are permitted to be over-expressed and thus drive processes for longer or in inappropriate situations leading to malignant growth.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