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
Regulation Of Tissue-type Plasminogen Activator Gene Expression In Endothelial Cells And In Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$244,009.00
Summary
Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how t ....Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how the t-PA gene is suppressed by TNF in human endothelial cells and in transgenic mice. The transgenic mice we have available express the regulatory region of the t-PA gene (called the gene promoter) connected to a reporter gene called LacZ. We will use these animals to visualise the expression pattern of LacZ expression under normal conditions and in mice treated with TNF. The results of these experiments will provide new information as to how the t-PA gene is controlled in cells and in the body.Read moreRead less
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inf ....Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a view to characterize genes critical for macrophage development. These genes may provide potential targets for new pharmacological agents.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
Functional Analysis Of Human MC1R Polymorphisms In Directing Melanocyte Phenotype
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
Sunsmart campaigns are a unifying element in the lives of many Australians who wish to ensure protection against the damaging effects of ultraviolet rays in sunlight. Indeed, Australians have the highest incidence of UV-induced melanoma in the world. Although it is evident that lighter skin colours are more susceptible to sun damage, the relationship between sun exposure, skin type and melanoma formation is less clear. An essential first step in understanding the complex interactions that give r ....Sunsmart campaigns are a unifying element in the lives of many Australians who wish to ensure protection against the damaging effects of ultraviolet rays in sunlight. Indeed, Australians have the highest incidence of UV-induced melanoma in the world. Although it is evident that lighter skin colours are more susceptible to sun damage, the relationship between sun exposure, skin type and melanoma formation is less clear. An essential first step in understanding the complex interactions that give rise to melanoma, and in identifying individuals that have a high susceptibility, is to reduce phenotypic analyses to genotypic classifications. As pigmentation phenotype is a factor of central importance in determining an individuals risk for melanoma, characterisation of the genes underlying the physical qualities of human eye, hair and skin colour will give a more direct and accurate genotypic assessment of risk. Results from an epidemiology study of melanoma patients in Queensland have identified a number of genetic changes within the melanocyte stimulating hormone receptor (MC1R) gene that associate with skin, hair and eye colour as well as with incidence of melanoma. Further investigation of MC1R gene alleles which segregate with skin and hair colours will provide the beginning for a whole new genotype-based classification of skin colour and melanoma risk, and will significantly contribute to our understanding of what makes some individuals highly susceptible to melanoma while others are not. Indeed, MC1R polymorphisms may numerically be the most important melanoma predisposition gene yet identified, exerting its effects as one of those common genes of small effect which may account for much more of the case load in melanoma than rarer genes of large effect. Studies such as this will enable powerful genotyping methods to be employed in identification of those individuals at highest risk for melanoma and other skin cancers.Read moreRead less
Structure-function Analysis Of Nuclear Receptor And Cofactor Action: Evidence For A Role In Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a pr ....Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.Read moreRead less