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.