High Resolution Genome-wide Genomic Analysis Of DCIS To Identify Genes Involved In Disease Initiation And Progression
Funder
National Health and Medical Research Council
Funding Amount
$543,370.00
Summary
DCIS is the most common type of noninvasive breast cancer and in some women may progress to malignant disease but little in know about how it develops. We will bring to bear our experience with cutting edge technology and access to extensive clinical resources to the analysis of a large series of pure DCIS with the aim of identifying previously unknown cancer causing genes. This data will lead to the identification of novel breast cancer genes that will assist clinical management.
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.Read moreRead less
Induction Of Reactive Oxygen Species By Hepatitis C Virus And Its Role In Liver Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that vira ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that viral proteins and viral replication play in the development of liver disease are not well characterized. Previous experiments in the laboratory have shown that one of the hepatitis C virus proteins results in the formation of toxic oxygen molecules known as a reactive oxygen species. This toxic oxygen molecules can have an effect on liver cells that may enhance the progression of the liver disease process in hepatitis C virus infected individuals. The role that these molecules play in liver cells is unknown but experiments are planned in laboratory model systems and in specimens obtained from hepatitis C virus infected individuals to further examine potential mechanisms. This will hopefully lead to the identification of new treatments for hepatitis C virus liver disease. Some patients with hepatitis C will develop liver cancer, however, all the reasons are not known. Using new technology known as microarray, a consequence of the human genome project, we have been able to look at the expression levels of thousands of genes in liver cancer. Experiments are planned to determine if these genes are important in liver cancer and if they can be used as targets for therapy or to more easily diagnose liver cancer.Read moreRead less
Site-specific Integration Of Functional Genomic Loci: Applications In Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$442,664.00
Summary
Gene therapy strategies have traditionally focused on the delivery of therapeutic genes by viral vectors. Mindful of the limitations and potential problems of viral gene delivery, non-specific viral integration and limited transgene expression, this investigation will explore the delivery and site-specific integration of large genomic fragments into human stem cells. It is anticipated this approach will avoid some of the problems associated with poor gene expression and insertional oncogenesis.
Genetic And Phenotype Studies Of Partial Epilepsy In Gypsies
Funder
National Health and Medical Research Council
Funding Amount
$646,136.00
Summary
Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies ....Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies have proved particularly difficult to understand and the numerous genetic studies conducted so far have failed to produce important and replicable results. It is becoming increasingly clear that enormous genetic heterogeneity, with many rare mutations occurring in different affected subjects, will be a major obstacle to understanding the molecular basis of complex epilepsies. In this context, genetically isolated populations, which stem from a small number of ancestors, can be particularly helpful and revealing, since their limited genetic diversity means that the number of genes involved in causing complex epilepsies may be smaller and shared between individuals and families. In this study, we will analyze affected families, as well as non-familial cases of epilepsy, from a genetically isolated population - the European Roma-Gypsies. We will determine the number of potential susceptibility genes involved in familial forms, the overlap and differences between families, as well as the contribution of the genes identified in families to the development of sporadic epilepsy.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
Dystrophin Gene Repair In Mdx Mouse Myoblasts And Bone Marrow Cells As A Basis For Autologous Transplant In Human DMD
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelch ....The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelchair confinement by early teens. DMD boys undergo major clinical and surgical treatments which at present only provide small but significant improvements to their lives. The median age at death for Duchenne boys is 22 years. The cause of DMD has been known for almost 2 decades and is a defect in just a single component of muscle, Dystrophin which is produced by muscle cells. In general, boys with DMD possess Dystrophin which is missing an important part that prevents the breakdown of muscles during activity. As a consequence, all the muscles in DMD boys slowly break down over their lifetime until they die because the muscle which helps in drawing breath (Diaphragm) is no longer capable of helping them to breathe. The muscle component Dystrophin is produced by a gene (the dys gene) and the defect of Dystrophin is caused by a defect in the dys gene. If the dys gene defect was able to be corrected in boys with DMD, their Dystrophin may also be corrected and the breakdown of their muscle prevented. We have been able to correct the dys gene in muscle cells from a mouse with DMD. We wish to improve this technology and allow muscle to be repopulated with genetically corrected cells to form a basis for treatment of human DMD. In this way we hope to significantly improve and lengthen these boys' lives and even lead to a cure for DMD and other genetic muscle diseases.Read moreRead less