Genetic And Bioinformatic Analysis Of Complex Human Diseases
Funder
National Health and Medical Research Council
Funding Amount
$8,752,567.00
Summary
Some human diseases are common in families; examples include prostate cancer, blood cancers, epilepsy and diabetes. Therefore, close relatives of individuals with a disease have an increased risk of being affected by this disease, implying a genetic basis. Finding the cause of these diseases is difficult, we will be developing novel approaches to the identification of genes responsible for these diseases. This is the first step towards the development of treatments for affected individuals.
Generation Of Mouse Models To Study The Roles Of Different Bcl-2 Family Members In The Regulation Of Apaptosis
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Programmed cell death, or apoptosis, is required for the removal of infected, damaged or unwanted cells and its disrupted regulation is implicated in cancer, autoimmunity and degenerative disorders. The Bcl-2 family of proteins are key regulators of apoptosis. We propose to generate several mouse models to better understand the relationships between the different members of the Bcl-2 family in an effort to control this pathway for therapeutic purposes.
Cystic fibrosis is a life-threatening disease of the lungs and digestive system. It is the most common single gene disorder of Caucasian populations and most of the moratility is caused by the presence of chronic lung infections, most notably with the bacterial pathogen, Pseudomonas aeruginosa. Despite the cystic fibrosis gene being discovered over 10 years ago we still have no clear indication as to how defects in the CF gene cause susceptibility to bacterial infections, and result in the infla ....Cystic fibrosis is a life-threatening disease of the lungs and digestive system. It is the most common single gene disorder of Caucasian populations and most of the moratility is caused by the presence of chronic lung infections, most notably with the bacterial pathogen, Pseudomonas aeruginosa. Despite the cystic fibrosis gene being discovered over 10 years ago we still have no clear indication as to how defects in the CF gene cause susceptibility to bacterial infections, and result in the inflammation of the lung. Our studies address this issue by examining thechanges of gene expression in response to infection with Pseudomonas aeruginosa and therefore provide us with routes to therapies which are targetted against CF gene mediated inflammation.Read moreRead less
Genes Controlling The Development Of Lung Disease In Normal And Cystic Fibrosis Mice.
Funder
National Health and Medical Research Council
Funding Amount
$362,582.00
Summary
Patients with cystic fibrosis have a lethal predisposition to bacterial infection which causes irreversible lung disease. It is clear that even when patients carry the same mutation in the defective gene (CFTR), genetic background influences the course of the disease. Very little is known of the nature of these other genes and this proposal will identify those genes which influence the response of the CF lung to pathogens and in doing so may indicate novel therapeutic strategies.
The Influence Of Alpha Actinins On Human Performance
Funder
National Health and Medical Research Council
Funding Amount
$542,500.00
Summary
There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to gener ....There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to generate maximal force at high speed. Similarly, the severity of muscle disease in an affected individual is influenced, in part, by other genes that affect normal muscle performance. The genes responsible for normal variations in muscle function in humans are unknown. The alpha-actinins are structural components of skeletal muscle. The two forms of alpha-actinin in skeletal muscle interact with a number of proteins involved in human muscle disease and thus likely contribute to the severity of muscle weakness in affected patients. Alpha-actinin-3 is present only in fast (type 2) fibres - the muscle fibres responsible for perfomance at high speed. We have identified a genetic change that results in absence of this protein in 1 in 5 people in the general population, without causing disease. We now have evidence that this genetic change, and hence whether or not muscle contains alpha-actinin-3, influences muscle performance in elite athletes. We will now use a variety of approaches to study the alpha-actinins in normal and diseased skeletal muscle. We will study the effect of changes (mutations) in the alpha-actinins in the muscle cells grown in the laboratory and in animal models. This work will impact on our understanding of how normal skeletal muscle functions, and the factors that influence human diversity in the general population.Read moreRead less
The Influence Of Alpha Actinins On Human Performance In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,989.00
Summary
We have identified a common genetic variation that results in absence of the fast muscle fibre protein, a-actinin-3, in over 1 billion people worldwide. Loss of a-actinin-3 influences elite athletic performance and skeletal muscle function in the general population by altering efficiency of muscle metabolism. We will now study mice and humans to determine how a-actinin-3 deficiency influences normal muscle function with age, response to exercise and the severity of human muscle disease.
The Genetic Control Of Platelet Production And Function
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by geneti ....Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by genetic mutations, viral infections, or by cancer treatments like chemotherapy. The only way to raise platelet numbers in a person with thrombocytopenia is a blood transfusion, which carries with it risks and potential side effects. While we understand quite a lot about how the body produces platelets, we don t know anywhere enough to be able to develop new treatments. Our work is focused on the identification of the genes that control the process, beginning with mouse models of thrombocytopenia, genome mapping, gene isolation, and finally, making the links between the newly identified genes and patients with thrombocytopenia. It will give us a much better understanding of how platelets are produced, how things go wrong in human disease, and how new therapies might be developed to treat them.Read moreRead less
First Generation Mouse Models Of MtDNA Disease: Testing Genotype/phenotype Predictions
Funder
National Health and Medical Research Council
Funding Amount
$256,527.00
Summary
Mitochondrial diseases comprise a diverse group of inherited diseases affecting infants, children and adults. These disorders result from defective energy production by the mitochondria, tiny structures in all cells which have their own unique DNA. This mitochondrial DNA is inherited only from our mothers. To make energy for cells to function normally, special enzymes are produced in the mitochondria from mitochondrial and nuclear genes. In their most severe form mitochondrial disease results in ....Mitochondrial diseases comprise a diverse group of inherited diseases affecting infants, children and adults. These disorders result from defective energy production by the mitochondria, tiny structures in all cells which have their own unique DNA. This mitochondrial DNA is inherited only from our mothers. To make energy for cells to function normally, special enzymes are produced in the mitochondria from mitochondrial and nuclear genes. In their most severe form mitochondrial disease results in infants with muti-system failure. Adult forms are less severe, with symptoms including epilepsy, cardiomyopathy, late-onset blindness or deafness, and commonly diabetes. We do not understand why different mitochondrial mutations result in such diverse symptoms, and no therapies have been consistently successful. Unusual features of mitochondrial DNA has meant that it has remained beyond the reach of techniques which are commonly used now to produce mice with altered genes. These so-called 'mouse models' are powerful tools to better understand human diseases and importantly, to enable experimental therapies to be tested and improved. This grant proposes a novel method of producing such mouse models, for the first time allowing mice with different levels of defective mitochondrial function to be produced to model the human diseases. In the proposed work, mitochondria from different mouse species will be introduced into laboratory mice. This unusual approach is based on previous work by the investigators who have shown that this produces defective mitochondria in cultured mouse cells. These mice will be allowed to age and the function of mitochondria from different organs tested as the animals age. Secondly, a range of mitochondrial DNA mutations will be produced in cultured cells and mutants selected to make other mice which should accurately model the diverse human diseases.Read moreRead less