Retrotransposon Regulation Of The Human Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$231,937.00
Summary
Complete sequencing of the human genome has revealed the positions of approximately 20,000 genes. In addition, nearly 50% of the human genome is comprised of repetitive sequences previously thought of as junk DNA. Numerous studies are now finding that this DNA actually has a variety of important functions, particularly in the control of gene activity. This project will examine the relationships between gene expression and nearby repetitive sequences during the innate immune response in humans.
The Role Of Ikaros In Establishing Regulatory Networks For Lymphocyte Development
Funder
National Health and Medical Research Council
Funding Amount
$345,809.00
Summary
Ikaros is a protein that regulates gene expression during development of lymphocytes from blood stem cells. Ikaros has a profound importance in normal and malignant lymphocyte development, but we still do not know how it controls these processes. The aim of my study is to identify genes regulated by Ikaros and the molecular mechanisms of their regulation. This study will contribute to understanding of the regulatory network controlling the development and function of lymphocytes.
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
In Vivo And In Vitro Studies Of The Human -308 TNF Promoter Polymorphism.
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarif ....The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarify some of these questions, we will generate genetically modified mice that have either of the two genetic forms of the human TNF promoter. These mice will be compared in two models of associated disease, murine Lupus and cerebral malaria. We will also characterise the interactions of TPF1 with other components of the TNF control region. An understanding of the role of TPF1 in controlling TNF expression and an appreciation of the cell types that are able to express the phenotype, will allow the development of more subtle, cell specific strategies to modulate the activity of TNF without completely abolishing expression and may lead to better preventative and therapeutic strategies.Read moreRead less
Functional Validation Of FoxP3 Target Genes In Human Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$545,341.00
Summary
Using DNA based technologies we have focused on rare white blood cells known as regulatory T cells. These cells are policeman of the immune system and are responsible for maintaining balanced immune reactions, and preventing attack against harmless substances. These cells prevent autoimmune disease in healthy individuals, and only by first understanding how they work normally can we investigate and correct the defects in autoimmune diseases such as type 1 diabetes.
Gene Transcription In Activated T Cells: A Model Of Chromatin Remodeling.
Funder
National Health and Medical Research Council
Funding Amount
$477,500.00
Summary
Cells of the immune system respond to invasion of the body by infectious or other damaging agents by switching on the production of a large array of proteins that are critical for an orchestrated immune response. Some of these proteins, referred to as cytokines, are secreted by the cells and act as intercellular messengers to affect the function of other cells need for an immune response. Switching on the production of these cytokines requires the genes that produce them to interpret the complex ....Cells of the immune system respond to invasion of the body by infectious or other damaging agents by switching on the production of a large array of proteins that are critical for an orchestrated immune response. Some of these proteins, referred to as cytokines, are secreted by the cells and act as intercellular messengers to affect the function of other cells need for an immune response. Switching on the production of these cytokines requires the genes that produce them to interpret the complex signaling pattern to which the cell has been exposed. These complex signaling patterns are interpreted in the nucleus by molecular switches that lie beside the genes in the DNA. The incorrect production of these proteins is involved in immune diseases such as autoimmunity, allergy and leukemia. Genes are housed in the nucleus of the cell, packaged into a structure known as chromatin. When the gene is not producing protein it is tightly packaged in chromatin but when it is activated to produce protein this packaging is altered to allow the gene to see the signals being received by the cell and produce protein. We have identified a protein within the nucleus that is critical in allowing certain cytokine genes to see the signals being received in the nucleus. By investigating the role of this protein (called c-Rel) in chromatin reorganization in immune cells, we hope to better define the steps required for appropriate gene activation in an immune response. This knowledge, in turn, will lead to the identification of novel therapeutic targets to control immune responsesRead moreRead less
Regulation Of Expression Of The MicroRNA-200 Family
Funder
National Health and Medical Research Council
Funding Amount
$573,557.00
Summary
The majority of deaths from cancer are due to tumour metastasis. To metastasize, tumour cells must convert to a migratory form that can allow tumor cells to migrate and disseminate in the body. This process requires a genetic reprogramming of the cell. We have discovered that this genetic reprogramming is under the control of small RNA molecules called microRNAs. In this project we investigate what controls the levels of the microRNAs, to allow metastasis to occur in colon tumours.
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
Osteoporosis is a pathological loss of bone that affects many Australians. It occurs because of an excessive release of calcium from bone that is caused by the overactivity of the cells that break down bone, osteoclasts. We have studied two genes that are involved in the way these cells work and by a close examination of the the way they are regulated we hope to understand how osteoclasts are derived and how their activity is controlled. In particular we will look at two newly dicovered osteocla ....Osteoporosis is a pathological loss of bone that affects many Australians. It occurs because of an excessive release of calcium from bone that is caused by the overactivity of the cells that break down bone, osteoclasts. We have studied two genes that are involved in the way these cells work and by a close examination of the the way they are regulated we hope to understand how osteoclasts are derived and how their activity is controlled. In particular we will look at two newly dicovered osteoclast regulators called PPAR-gamma and PPAR-delta. These offer the opportunity for the development in the future of new, alternative drugs for the treatment of osteoporosis.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