Identifying Novel Genes Causing Cytochrome C Oxidase (COX) Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$426,917.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This study focuses on the mitochondrial disorder cytochrome c oxidase (COX) deficiency, for which we have diagnosed 80 Australian patients. COX requires 13 separate components to be assembled together in order to work properly, but mutations in the genes encoding these components are not present in most patients. We believe that the most common problems will be in genes involved in assembling the components rather than in the components themselves. We will use a number of methods to pinpoint where in the genome the disease genes are located. A key to our strategy is identifying patients likely to have mutations in the same gene. We have identified two such groups, and will do studies that involving fusing two cell lines together to confirm they have the same disorder. We will then perform genetic mapping to look for regions of similarity in the genome using DNA (SNP) chips. We will test how well the genes in such regions are expressed, whether we can correct the problem in cultured skin cells by introducing a healthy copy of that chromosome, and look for gene mutations. Identifying these genes will allow us to improve future diagnosis and prevention and may allow us to develop new methods of treatment. Milder mitochondrial problems also contribute to a range of more common diseases such as diabetes and Alzheimer disease, so any new treatments could potentially have wide applicationRead moreRead less
Identifying Target Genes For Novel Anti-epileptic Therapies In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$469,802.00
Summary
Epilepsy is a disease which affects 2-4% of the population. There are a wide range of drugs available to treat the condition but there is consistently 30-40% of patients who do not respond well to any of these drugs and who continue to have seizures. The reason that there are no drugs available for these people is that most of the drugs available have been designed along the same principles. A new set of principles is needed to develop new drugs which will be able to treat those people not respo ....Epilepsy is a disease which affects 2-4% of the population. There are a wide range of drugs available to treat the condition but there is consistently 30-40% of patients who do not respond well to any of these drugs and who continue to have seizures. The reason that there are no drugs available for these people is that most of the drugs available have been designed along the same principles. A new set of principles is needed to develop new drugs which will be able to treat those people not responding to current therapy. This project is designed to identify new biologic pathways which may be interrupted with drugs to prevent seizures in people with epilepsy. This project uses a procedure to induce mutations into genes in mice and then screens for mice which do not seize when challenged with a drug which generates seizures in mice. Genetic studies will identify the mutated genes and these will be used as potential targets for new therapies or will identify new biological pathway which should expand the use of future anti-epileptic drugs.Read moreRead less
Microarray-targeted Candidate Gene Approach To Finding Ovarian Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$612,933.00
Summary
We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them t ....We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them to be targeted for screening, and for intervention studies, as well as providing fundamental insight into the etiology of ovarian cancer.Read moreRead less
Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the ....Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the identification of the genetic basis of the disease has proved exceedingly difficult, with numerous studies producing no definitive data. The lack of convincing results has been interpreted as an indication of complex genetic mechanisms and underlying differences between affected families and ethnic groups. Genetically isolated populations, where most individuals descend from a small number of founders, are believed to hold great potential for understanding the genetic basis of complex diseases, such as bipolar disorder. Affected subjects in such populations are likely to share the same predisposing genes, making these genes easier to identify. During the last 10 years, we have been involved in the study of bipolar disorder in one such population, with very promising results. In this project, we propose to take the research further by collecting more affected families, confirming the current positive findings and narrowing down the search to a small region, possibly a single gene. If successful, the study will be a major breakthrough which, by identifying a molecular pathway and disease mechanism, will contribute valuable and generally valid information on the biological basis of mood disorders.Read moreRead less
Molecular Genetics Of The Host Response Defect In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$564,690.00
Summary
Cystic fibrosis is the most common lethal genetic disease in Caucasian populations. Affected individuals suffer from a number of symptoms but the most serious is a chronic infect with the bacterial pathogen Pseudomonas aeruginosa. The sustained lung inflammation caused by infection with Pseudomonas aeruginosa ultimately destroys the structure of the lung to the point where it can no longer function. Gene therapy has been suggested as a possible treatment for the disease but another approach is t ....Cystic fibrosis is the most common lethal genetic disease in Caucasian populations. Affected individuals suffer from a number of symptoms but the most serious is a chronic infect with the bacterial pathogen Pseudomonas aeruginosa. The sustained lung inflammation caused by infection with Pseudomonas aeruginosa ultimately destroys the structure of the lung to the point where it can no longer function. Gene therapy has been suggested as a possible treatment for the disease but another approach is to identify the CF specific aspects of the inflammatory response and target those for therapeutic development. In our previous work we have identified several strong candidates for the inflammatory molecules in the CF lung and in this application we will test those candidates to see whether they play a major role in CF lung disease.Read moreRead less
Fine Mapping Of A Significant Linkage Region For Endometriosis
Funder
National Health and Medical Research Council
Funding Amount
$518,250.00
Summary
Endometriosis is a common disorder affecting up to 10% of women. In this condition, a special type of tissue that normally lines the inside of the womb (the 'endometrium') starts to grow outside the womb, mostly in the pelvis (lower abdomen). Common symptoms are severe pelvic pain, menstrual problems and infertility. The disease has a major impact on women's health, relationships, productivity and life choices. The mechanisms that cause endometriosis are not well understood. Genetic factors infl ....Endometriosis is a common disorder affecting up to 10% of women. In this condition, a special type of tissue that normally lines the inside of the womb (the 'endometrium') starts to grow outside the womb, mostly in the pelvis (lower abdomen). Common symptoms are severe pelvic pain, menstrual problems and infertility. The disease has a major impact on women's health, relationships, productivity and life choices. The mechanisms that cause endometriosis are not well understood. Genetic factors influence a woman's risk of developing endometriosis and finding genes and pathways leading to this disease would be a major advance. This will help design better approaches for the diagnosis, prevention and treatment of endometriosis. Since 1996, nearly 4,000 women with endometriosis plus their families have joined our genetic study. This includes around 1,000 families with two or more sisters who both have the disease. We have looked at the DNA from these sisters and found significant evidence for a gene or genes affecting endometriosis on one chromosome. No one else has linked this location with endometriosis. We are now focusing our efforts in the laboratory on this area, which contains approximately 250 genes. The aim of our new project is to study genes in the region in more detail to pinpoint the gene or genes responsible for risk of endometriosis.Read moreRead less
Noncoding RNAs As Prognostic Markers And Therapeutic Targets In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$550,283.00
Summary
Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our labo ....Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our laboratory and others have shown that most of our genome and that of other mammals is actually expressed as noncoding RNA, which appears to be developmentally regulated. These RNAs (of which there appear to be tens of thousands, well outnumbering the protein-coding mRNAs) have been referred to as the hidden layer or dark matter of our genome, as they have barely been studied, but appear to play a central role in both normal and abnormal development in humans. There is now increasing evidence that many noncoding RNAs, including small regulatory RNAs called microRNAs, are perturbed in cancer and that these perturbations may be directly involved in, and be an accurate indicator of, cancer state and the direction of cancer progression. If this is true we need to understand the expression and functions of these RNAs in order to develop better diagnostics and perhaps powerful new therapeutics for cancer, based on RNA technology and generic delivery systems. This project will explore the patterns of noncoding RNA expression in normal breast development and in breast cancer, to identify those RNAs that direct or accompany the differentiation of these tissues, and to test the effects of interfering with their expression on these processes. These foundation studies lie at the leading edge of a new understanding of human genetics and cancer, and will provide a platform for future applications in medicine that utilize this information and understanding.Read moreRead less