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
Detection Of Alternative Lengthening Of Telomeres In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate ....In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate themselves many times, and therefore they need to find a method to prevent their telomeres shortening. We discovered one such method, called Alternative Lengthening of Telomeres (ALT), that is used by some cancers. It has been shown in principle that cancer cells can be killed by disrupting their ability to prevent telomere shortening. Therefore, in another project we are developing methods needed to find drugs that inhibit ALT. In the meantime, we have found the first evidence that some normal cells have an ALT-like mechanism. Our speculation is that cancer cells are able to dysregulate and subvert this normal mechanism in order to prevent their telomeres from shortening. In this project, we will analyse the ALT-like mechanism in mice, to determine its characteristics, and to determine what tissues use it. This information will provide critically important insights into the ALT mechanism itself, and the likely side effects of drugs that inhibit ALT.Read moreRead less
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
The genomics of adaptation in Wolbachia pipientis, an emerging biocontrol agent. Australians are increasingly exposed to insect-transmitted diseases such as dengue fever. Novel biocontrol methods using the bacterium Wolbachia aim to control insect populations to reduce disease transmission. Our research will be the first to investigate genomic variation and the process of adaptation to new insect hosts in Wolbachia. The novel data and understanding of evolutionary processes we generate will be c ....The genomics of adaptation in Wolbachia pipientis, an emerging biocontrol agent. Australians are increasingly exposed to insect-transmitted diseases such as dengue fever. Novel biocontrol methods using the bacterium Wolbachia aim to control insect populations to reduce disease transmission. Our research will be the first to investigate genomic variation and the process of adaptation to new insect hosts in Wolbachia. The novel data and understanding of evolutionary processes we generate will be critical for screening bacterial biocontrol candidates and designing biocontrol release strategies. It will also strengthen the position of Australian research as a world-leader in the fusion of post-genomics and applied microbiology. Read moreRead less
A comparative genomics approach to understanding host-endosymbiont interactions. Australia's unique ecosystems are vulnerable to invasion by exotic pests that threaten agriculture and human health. The bacterial symbiont Wolbachia is found in many major pests of agricultural and medical importance. Our results will give insights into how Wolbachia spreads into host populations and improve its use as a tool to impair insect transmission of disease, e.g. as an agent to carry genes into an insect p ....A comparative genomics approach to understanding host-endosymbiont interactions. Australia's unique ecosystems are vulnerable to invasion by exotic pests that threaten agriculture and human health. The bacterial symbiont Wolbachia is found in many major pests of agricultural and medical importance. Our results will give insights into how Wolbachia spreads into host populations and improve its use as a tool to impair insect transmission of disease, e.g. as an agent to carry genes into an insect population that limit disease transmission. Our results will also make fundamental contributions to understanding host-parasite evolution, host-parasite communication, and insect developmental processes, and will be of interest to a large international community of researchers in this field. Read moreRead less
Diseases Of Aminoacid Transport: Genetic, Molecular And Biochemical Studies
Funder
National Health and Medical Research Council
Funding Amount
$394,173.00
Summary
Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hart ....Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hartnup disease is an inherited disorder of neutral aminoacid transport that can lead to a sun-sensitive skin rash, difficulties in controlling movements and walking and other neurological symptoms including mental retardation. A major feature of Hartnup disease is its clinical variability. We have recently identified the main genetic cause for Hartnup disease, and named the gene SLC6A19. We wish to examine whether the clinical variability observed is a consequence of genetic changes and variability in SLC6A19 and other possible genes. Two other aminoacidurias to be studied are dicarboxylic aminoaciduria and iminoglycinuria; both of which are also variable in their clinical consequences ranging from normality to mental retardation. Owing to the relative rarity of these disorders, we are fortunate to have exclusive access to individuals identified by the largest neonatal screening programme for aminoacidurias in the world, based in Canada, and other clinical cohorts within Australia. We will undertake genetic testing to localise and-or confirm the gene(s) involved in these diseases for the first time anywhere and then seek to explain their clinical variability based on functional analyses. We have established a team of researchers with complementary skills from three sites comprising the Australian Aminoaciduria Consortium. Outcomes from this project should impact on the causes and possible therapies for other important medical diseases including motor neurone disease.Read moreRead less
Australian Laureate Fellowships - Grant ID: FL200100068
Funder
Australian Research Council
Funding Amount
$3,328,974.00
Summary
Australian wild animals: environmental change and quantitative genomics. This project aims to determine the effects of changing environments on wild animal populations across Australia. By combining recent advances in genomic technology with a consortium of fourteen long-term studies of mammals, birds and reptiles, it aims to quantify the genetic basis of life-history variation and the potential for evolutionary adaptation in the wild. The project will generate a comprehensive understanding of t ....Australian wild animals: environmental change and quantitative genomics. This project aims to determine the effects of changing environments on wild animal populations across Australia. By combining recent advances in genomic technology with a consortium of fourteen long-term studies of mammals, birds and reptiles, it aims to quantify the genetic basis of life-history variation and the potential for evolutionary adaptation in the wild. The project will generate a comprehensive understanding of the genetic consequences of environmental change, population decline, inbreeding and disease in natural environments. The expected benefits include a coordinated network for long-term wild animal studies in Australia, advanced quantitative skills training, and knowledge transfer for wildlife management and conservation.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE210100549
Funder
Australian Research Council
Funding Amount
$417,328.00
Summary
Adaptive evolution and its demographic consequences today. This project aims to provide the first test of whether the rate of adaptative genetic evolution has changed in the recent decades, to quantify how much recent genetic evolution helps animal populations survive, and to increase the ability to study on-going genetic evolution in Australian wildlife. The project is of major significance as many species are currently threatened, or invading, due to rapid environmental changes, in particular ....Adaptive evolution and its demographic consequences today. This project aims to provide the first test of whether the rate of adaptative genetic evolution has changed in the recent decades, to quantify how much recent genetic evolution helps animal populations survive, and to increase the ability to study on-going genetic evolution in Australian wildlife. The project is of major significance as many species are currently threatened, or invading, due to rapid environmental changes, in particular climate change. The anticipated outcome of the project is to deliver new methods, establish a network of international and national collaborators and improve the ability to measure and to forecast how Australian animals adapt to rapidly changing environments.Read moreRead less