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
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
Conditional Knockout Of The Murine Patched Gene For The Study Of Skin Differentiation And Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$423,564.00
Summary
Basal cell carcinoma (BCC) is the most common cancer in Australia. We recently isolated the BCC gene, Patched (PTCH) from analysis of patients with Naevoid Basal Cell Carcinoma Syndrome (NBCCS). Individuals with NBCCS have a wide variety of developmental defects in addition to a cancer predisposition which includes medulloblastoma, rhabdomyosarcoma and ovarian fibroma as well as multiple BCCs. This application proposes the generation of an animal model for skin development and cancer by selectiv ....Basal cell carcinoma (BCC) is the most common cancer in Australia. We recently isolated the BCC gene, Patched (PTCH) from analysis of patients with Naevoid Basal Cell Carcinoma Syndrome (NBCCS). Individuals with NBCCS have a wide variety of developmental defects in addition to a cancer predisposition which includes medulloblastoma, rhabdomyosarcoma and ovarian fibroma as well as multiple BCCs. This application proposes the generation of an animal model for skin development and cancer by selectively removing patched gene function from specific cell of the skin. In doing this we will be able to determine the exact role of this gene in skin development, and how mutation causes common skin cancer.Read moreRead less
Polycomb Group Genes In Murine Lymphomagenesisand Their Impact On Drug Response.
Funder
National Health and Medical Research Council
Funding Amount
$476,815.00
Summary
The success of lymphoma treatment with current drugs is limited by drug resistance. Some crucial links between genes which cause cancer and genes which alter response to cancer treatment have been identified: the cellular machinery that cancer cells use to become cancer cells in the first place, is often the same machinery that cancer cells later use to become resistant to cancer treatments. The Polycomb Group family controls expression of other critical genes: that is, they dictate which genes ....The success of lymphoma treatment with current drugs is limited by drug resistance. Some crucial links between genes which cause cancer and genes which alter response to cancer treatment have been identified: the cellular machinery that cancer cells use to become cancer cells in the first place, is often the same machinery that cancer cells later use to become resistant to cancer treatments. The Polycomb Group family controls expression of other critical genes: that is, they dictate which genes are switched on, where, and when. This determines whether a cell behaves normally or whether it may turn into a cancer cell. When Polycomb Group genes themselves are expressed at the wrong time or place, they can cause cancer. In human lymphoma, these genes have been associated with more aggressive lymphoma. This has also been shown for other cancers such as breast and prostate cancer. In some cases these genes are associated with cancers that do worse following anti-cancer treatment. So far, no research has been published looking the direct impact of the Polycomb Group genes on the success of treatment in a controlled laboratory model. We have used a powerful laboratory mouse model of lymphoma, established in the host laboratory, in which over-expression of the c-myc oncogene in developing B cells causes lymphoma. This model is easy to manipulate and this provides us with a great deal of experimental control, much more than can be achieved from working with patient samples. Two family members, Bmi-1 and Cbx7, cause lymphoma to develop aggressively and we will ask whether two other members, Ezh2 and Rybp do this as well. We will determine whether these 4 genes cause drug resistance in lymphoma, with currently used chemotherapy and also with novel anti-cancer drugs. By increasing our understanding of drug resistance in lymphoma, drugs may be utilised more effectively and new markers identified to predict which drug will be successful in treating a particular lymphoma.Read moreRead less
The Identification Of Male Meiosis Genes Using A New Mouse Line And Human Genome Scans For Gene Copy Number Variations
Funder
National Health and Medical Research Council
Funding Amount
$604,793.00
Summary
Infertility affects 1 in 25 Australian men and meiosis is a key process in male fertility, yet we know very little about the mechanisms that control it. We will use a new point mutant mouse model of meisois failure to identify a novel regulator of male fertility. Further, we hypothesize that changes in gene copy number will lead to meiosis arrest and infertility in some men. Such variations will be assessed through a whole genome scan of a unique set of infertile men.
Investigating The Role Of The Notch4 Receptor In Blood Vessel Formation And Remodelling In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$653,086.00
Summary
We aim to understand how blood vessels form. This process is crucial for foetal development, and for injury repair in adults. When there is too much or too little blood vessel formation, diseases such as arthritis, blindness and osteoporosis can result. Also many tumours grow and spread by growing new blood vessels. We will study a signal that occurs between cells (Notch signalling) that is important in controlling the amount of blood vessel formation, by analysing in detail one component (Notch ....We aim to understand how blood vessels form. This process is crucial for foetal development, and for injury repair in adults. When there is too much or too little blood vessel formation, diseases such as arthritis, blindness and osteoporosis can result. Also many tumours grow and spread by growing new blood vessels. We will study a signal that occurs between cells (Notch signalling) that is important in controlling the amount of blood vessel formation, by analysing in detail one component (Notch4)Read moreRead less
Interactions Between Hedgehog And Ras Signaling In Lung Adenocarcinoma
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Lung cancer is a common and lethal disease in our community. In this project, we explore how signaling pathways that regulate the development of the lung in embryos contribute to the initation and progression of lung cancer. To do this, we use a mouse model of lung cancer in which we can activate embryonic signaling pathways in adult mice to study there effect on the disease. Understanding these pathways will help us to better treat and prevent lung cancer in humans.
Genetic Control Of Susceptibility To Autoimmune Gastritis
Funder
National Health and Medical Research Council
Funding Amount
$346,945.00
Summary
Autoimmune gastritis is caused by the immune system targeting and destroying the stomach lining. We have developed a mouse model of the causes of gastritis and mapped the two major genes that can control susceptibility. This project involves the final stages of identifying these genes and determining how they cause disease.
Targeting Critical Nodes On The IGF1-PI3K Pathway To Improve Function Of The Failing Heart
Funder
National Health and Medical Research Council
Funding Amount
$512,947.00
Summary
Heart failure is a major clinical problem which is becoming worse as our population grows older and comorbidities such as obesity and diabetes become more prevalent. Current heart failure therapeutics largely delay disease progression. This research proposal focuses on strategies designed to improve function of the failing heart, as opposed to simply delaying disease progression. This approach will lead to the development of new therapeutics.