Analysis Of Factors Governing Globin Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$512,996.00
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, fetal hemoglobin. We have identified key factors important for fetal gene expression. Our goal is to translate these findings into therapies for the hemoglobin disorders.
Identification Of Novel Mechanisms Governing Stage-specific Regulation Of The Human Globin Genes
Funder
National Health and Medical Research Council
Funding Amount
$481,826.00
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 worldwide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, fetal hemoglobin. We have identified key factors important for fetal gene expression. Our goal is to translate these findings into therapies for the hemoglobin disorders.
Characterisation Of Erythropoietic Mutants Identified In A Forward Genetic Screen In Mice.
Funder
National Health and Medical Research Council
Funding Amount
$501,902.00
Summary
The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cell ....The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cells are identified. The responsible genetic mutation is identified and the gene is then studied to determine how it influences red blood cell production. The results of these studies provide insights into a variety of human conditions including anemia, thalassemia and sickle cell disease.Read moreRead less
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
Removal of the nucleus from red blood cells (enucleation) is essential for proper circulation of red blood cells through the microvasculature and high haemoglobin concentration in the blood. How this fundamental process is achieved is surprisingly poorly understood. Here we propose to investigate how enucleation occurs in light of enucleation being an unusual asymmetric division. These studies are likely to lead to improvements in expansion of human red blood cells in vitro for transfusions.
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 fetus, fetal hemoglobin. We have identified a key factor important for fetal gene expression. We will now determine whether manipulation of this factor can cure hemoglobin disorde ....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 fetus, fetal hemoglobin. We have identified a key factor important for fetal gene expression. We will now determine whether manipulation of this factor can cure hemoglobin disorders.Read moreRead less
Transcriptional And Cell Cycle Control Of Erythropoiesis By E2F4
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
The balance in the number of cells in our body is a carefully regulated process which, when disturbed, can lead to a number of life-threatening diseases such as cancer. Through genetic studies in the mouse, we previously identified E2F4 as a protein that is required for the correct number of red blood cells in the body. Lack of E2F4 results in anaemia in the mouse embryo. We have studied these mice as a model to understand how cell production in the body can be controlled. In recent studies, we ....The balance in the number of cells in our body is a carefully regulated process which, when disturbed, can lead to a number of life-threatening diseases such as cancer. Through genetic studies in the mouse, we previously identified E2F4 as a protein that is required for the correct number of red blood cells in the body. Lack of E2F4 results in anaemia in the mouse embryo. We have studied these mice as a model to understand how cell production in the body can be controlled. In recent studies, we have identified proliferation defects and in particular cell division cycle defects as the major cause for the decreased production of red blood cells in the embryo. In addition, we have utilised gene microarray technology to survey which genes change in the absence of E2F4 by comparing gene expression profiles in normal and E2F4 deficient mice. These studies have identified a large number of genes that could be molecular targets for E2F4 and whose defective expression could be ultimately responsible for the anaemia of these mice. Importantly, our data suggests a completely novel function for E2F4 in controlling the switching on of genes required for cell division. In this proposal, we describe approaches to characterise how E2F4 controls the cell division cycle to identify the exact process(es) it may control such as DNA replication or separation of chromosomes into daughter cells. We will also test our hypothesis for a novel role for E2F4 in being able to switch on genes in nucleated red blood cell. Finally, we describe gene microarray experiments and a new promoter microarray approach to close in on the molecules directly required for the E2F4 control of red blood cell production. Because defects in the E2F family of proteins or the proteins that regulate them, the retinoblastoma, pRB family, have been implicated as central for cancer development, these studies will have broad implications for therapeutic targeting of this pathway in cancer.Read moreRead less
A Novel Genetic Element Controlling Adult Hemoglobin Production
Funder
National Health and Medical Research Council
Funding Amount
$493,907.00
Summary
Disorders of the blood protein hemoglobin are the commonest genetic diseases worldwide, and include thalassemia and sickle cell disease. In this proposal we study two novel mouse lines that exhibit thalassemia, but lack any of the known genetic mutations that cause this disease. These mice afford us the opportunity to make unique observations into how hemoglobin is produced, and thereby provide a platform for new therapeutic approaches in these devastating diseases of the blood.
Sickle Cell Disease was the first molecular disease described in man, and is the most prevalent. In some African countries, India and the Middle East, up to 20% of the population carry the sickle gene mutation. In developing countries, 90% of children die before 5 years of age. In developed countries, patients suffer a lifetime of chronic pain and die ~20 years early. We will employ new gene editing approaches to repair the mutation or recruit fetal hemoglobin to cure SCD in human samples.