Genetic Variation Of Mitochondrial Complex I: Its Role In Rare And Common Diseases
Funder
National Health and Medical Research Council
Funding Amount
$628,415.00
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 grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 46 separate components to be assembled together in order to work properly, but mutations in the 46 genes encoding these components only seem to explain disease in about half of all patients. Our aim is to identify new disease genes and to determine whether some patients have mutations in two different genes that interact to cause disease, rather than in a single gene. We will use a number of methods to pinpoint where in the genome the causative genes are located and then home in on the exact changes in the genes that cause disease. Identifying these genes will allow us to improve future diagnosis and prevention of mitochondrial disease. We will also generate mice in which one of the Complex I genes has been knocked out. These mice will allow us to better understand the basic disease mechanisms that link gene changes to disease. Understanding the basic biology may allow us to develop new methods of treatment. The mouse models will also be useful for trialling new treatments and for investigating the role of milder mitochondrial problems in common diseases such as diabetes and Parkinson disease. Any new treatments could potentially have wide application.Read moreRead less
Senataxin, A Novel Protein Involved In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. T ....The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. This disorder is called ataxia with oculomotor apraxia type 2 or AOA2. This condition develops in the teenage to early twenties and as the name suggests is characterised by loss of control of gait together with difficulties of eye movement. It is due to reduced function of a particular region of the brain called the cerebellum responsible for controlling movement. We have initial data suggesting that cells from these patients are very sensitive to environmental chemicals and their capacity to carry out repair of damage to DNA is compromised. We will investigate the nature of the defect at the molecular level and establish the function of the protein defective in this syndrome. This information will be important to determining specific therapies for AOA2 patients and may also have relevance to other neurodegenerative disorders.Read moreRead less
Regulation And Role Of Transcription At The Centromere.
Funder
National Health and Medical Research Council
Funding Amount
$737,801.00
Summary
Every human cell has 46 chromosomes. Chromosomes are structures that carry genes in all our cells. The centromere is an essential component of a chromosome. It controls the process of cell division, and it ensures the equal division of the duplicated chromosomes. Defects in centromere function can result in various genetic diseases and development of cancers. The structure of the centromere is unique and its properties are determined by an array of proteins and other as yet unknown factors that ....Every human cell has 46 chromosomes. Chromosomes are structures that carry genes in all our cells. The centromere is an essential component of a chromosome. It controls the process of cell division, and it ensures the equal division of the duplicated chromosomes. Defects in centromere function can result in various genetic diseases and development of cancers. The structure of the centromere is unique and its properties are determined by an array of proteins and other as yet unknown factors that bind to it. In our preliminary work, we have demonstrated that a novel non-protein component in the form of RNA (which are expressed products of genes) is essential for the binding of key proteins to the centromere. The presence and importance of such an RNA component has not been previously suspected and represents an exciting new mechanism that help to determine the functional and structural integrity of the centromere. In this project, we propose to study the details of this RNA and to define how this RNA-related mechanism operates to ensure the proper assembly and function of the centromere during cell division.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