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
Identification Of Novel Mechanisms Governing Stage-specific Regulation Of The Human Globin Genes
Funder
National Health and Medical Research Council
Funding Amount
$577,889.00
Summary
Hemoglobin is the major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production are the commonest genetic diseases world-wide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, embryonic hemoglobin. We have identified a key factor important for fetal gene expression. Our goal is to translate these findings into therapies for the globin disorders.
STUDIES OF NF-E4, A NOVEL FETAL/ERYTHROID SPECIFIC FACTOR INVOLVED IN FETAL GLOBIN GENE REGULATION
Funder
National Health and Medical Research Council
Funding Amount
$753,810.00
Summary
Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated ....Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated clinical course. Therefore, treatment strategies which could reactivate fetal globin gene expression after birth should be explored for these diseases. To achieve this goal we must further our understanding of the normal mechanisms of developmental regulation of globin gene expression. To this end we have recently identified a novel gene which is critical for fetal globin expression. The studies we propose here will further define the function of this gene and assess its potential for gene therapy for sickle cell disease and thalassemia.Read moreRead less
Microarray-targeted Candidate Gene Approach To Finding Ovarian Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$612,933.00
Summary
We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them t ....We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them to be targeted for screening, and for intervention studies, as well as providing fundamental insight into the etiology of ovarian cancer.Read moreRead less
The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
Transcriptome Profiling Of The Human Pathogen Schistosoma Japonicum
Funder
National Health and Medical Research Council
Funding Amount
$257,560.00
Summary
The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different g ....The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different genes, and to determine where and when they are active, thus placing the mass of data generated by genome sequencing programs into a biological and functional context. Microarrays provide a unique, cutting-edge, tool for investigating schistosome biology. We have fabricated a microarray representing some 20,000 schistosome genes. We will use this resource to perform large scale monitoring of schistosome gene expression during the parasite's complex life cycle, targetting the regionally important Asian schistosome, Schistosoma japonicum, for study. This will provide the single largest insight into the genetic changes that occur during schistosome development, will greatly further our understanding of the adaptations needed for the growth, development and survival of the parasite, and will identify genes involved in key biological processes, all of which may be exploitable for future interventions and treatments.Read moreRead less
Functional Significance Of ATM-dependent Phosphorylation Of Mre11
Funder
National Health and Medical Research Council
Funding Amount
$211,500.00
Summary
The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The in ....The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The intention here is to investigate some of the normal mechanisms of cellular response to radiation and determine why they are deficient in cells from individuals with these rare syndromes. We will focus on a protein, ATM, which is activated by radiation and on one of its substrates Mre11. Both molecules are involved in sensing and transmitting signals from DNA to cell cycle checkpoints. The expected outcome of this study is a greater understanding of the intricate set of signaling pathways that are activated in response to radiation damage. In addition it is expected that a detailed knowledge of these pathways and what goes wrong in specific disease states will be of assistance in understanding risk of developing cancer. Finally this information will also be useful in the design of novel compounds for the prevention and-or treatment of cancer.Read moreRead less
MicroRNA Networks That Safeguard The Functional Program Of Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,941.00
Summary
A newly discovered group of molecules termed microRNAs are thought to function as rheostats for the activity of genes. We have shown that these molecules are critical for the function of an immune cell type termed regulatory T cells. Without these cells, the immune system is unable to prevent uncontrolled and destructive inflammation. This proposal aims to utilize diverse technologies to uncover the precise molecular mechanisms by which microRNAs safeguard the function of regulatory T cells.