The Function Of BHLH Factors In Adult Haemopoiseis
Funder
National Health and Medical Research Council
Funding Amount
$595,353.00
Summary
Understanding how genes control the behaviour of bone marrow stem cells is currently needed for improving recovery after chemotherapy or bone marrow transplantation and in the future, will aid the application of new stem cell-based therapies for human diseases such as leukaemia. This research will examine how 2 closely related genes control bone marrow stem cell growth and the decision between beocoming a red cell or a white cell.
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.
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.
Regulation Of Red Blood Cell And Platelet Formation By BHLH Proteins
Funder
National Health and Medical Research Council
Funding Amount
$422,600.00
Summary
Continuous production of normal blood cells by the bone marrow is a process critical to human life. Disruption of this process leads to diseases such as leukemia, aplastic anemia and myelodysplasia which have devastating consequences for affected patients. Pivotal to understanding these diseases is a knowledge of the regulation of normal blood production. Our laboratory works on a gene known as SCL that is critical for blood formation. We have recently shown that loss of SCL in adult bone marrow ....Continuous production of normal blood cells by the bone marrow is a process critical to human life. Disruption of this process leads to diseases such as leukemia, aplastic anemia and myelodysplasia which have devastating consequences for affected patients. Pivotal to understanding these diseases is a knowledge of the regulation of normal blood production. Our laboratory works on a gene known as SCL that is critical for blood formation. We have recently shown that loss of SCL in adult bone marrow leads to abnormalities in two types of blood cells, the red blood cells and the platelets. This grant will extend this important observation to understand how the production of these cells is altered and what is its consequence. Our studies will help clarify the basis of blood cell formation and may impact on how we diagnose and treat a wide variety of blood disorders.Read moreRead less
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.
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
Activation Mechanisms Of The Hypoxia Inducible Factor-1a (HIF-1a) And The HIF-Like-Factor
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question ....A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question is how the cells sense they are in a low oxygen environment and by what mechanisms they initiate genetic reprogramming. We are studying two proteins which have the ability to alter activity of genes when cells are stressed by hypoxia (low oxygen), and seek to discover how the proteins switch from latent forms to active forms in response to hypoxia. A greater understanding of the molecular mechanisms involved in the cellular hypoxic response is important to the development of new therapeutics for disease states involving disrupted oxygen flow (eg heart attack and stroke). Drugs which would block the hypoxic induced development of blood vessels could also be extremely beneficial in cancer treatment, as blocking blood supply to growing tumours can result in their starvation and shrinkage.Read moreRead less
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
The Role Of The PRB/E2F Pathway In Erythropoiesis And Cell Cycle Control
Funder
National Health and Medical Research Council
Funding Amount
$272,036.00
Summary
Circulating blood contains two major types of cells. Red blood cells supply the oxygen required by all cells in our body to survive and white blood cells protect our body from invasion by foreign organisms. The balance in the number of these cells in our blood is a carefully regulated process which, when disturbed, can lead to a number of life-threatening blood diseases. Uncontrolled overgrowth of blood cells results in a particular type of cancer known as leukaemia. In contrast, when there is a ....Circulating blood contains two major types of cells. Red blood cells supply the oxygen required by all cells in our body to survive and white blood cells protect our body from invasion by foreign organisms. The balance in the number of these cells in our blood is a carefully regulated process which, when disturbed, can lead to a number of life-threatening blood diseases. Uncontrolled overgrowth of blood cells results in a particular type of cancer known as leukaemia. In contrast, when there is an insufficient number of red blood cells, not enough oxygen reaches cells from the brain and other vital organs and results in a condition known as anaemia. We have genetically engineered a mouse that lack the protein known as E2F4 and is unable to produce enough red blood cells and suffers from anaemia. This protein, E2F4, controls genes essential for the decision of cells to start or stop growing and multiplying. The E2F4-deficient mice therefore provide a new and powerful model to understand the mechanism by which disturbance of red blood cell numbers can lead to diseases such as leukaemia and other diseases of the blood. Identification of the genes controlled by E2F4 may provide new targets for the development of therapeutic drugs to combat these diseases.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