Genetic Approaches To Understand How Imbalanced Cytokine Signalling Drives The Pathogenesis Of Emphysema
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
Emphysema is a major component of Chronic Obstructive Pulmonary Disease (COPD), the fifth leading cause of death in Australia for which there is no effective treatment. We have discovered a specific mutation in a gene called gp130 that results in the formation of emphysema in mice. This finding allows us to understand the exact mechanisms by which this mutation causes emphysema, and therefore has the potential to uncover new strategies to design novel therapies against emphysema in humans.
Cross-talk Between Cytokine And Pathogen Recognition Receptor Networks In The Pathogenesis Of Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$174,800.00
Summary
Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly death of several thousand people in Australia alone. We have discovered a specific mutation in a gene called gp130 that results in the formation of gastritis and stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in chronic inflammation and the subsequent uncontrolled growth of epithelial cells that line the stomach wall.
Genetic Analysis Of Cell Death Pathways, Drug Resistance And Oncogenic Co-operativity In IL-3 Dependent Cell Lines
Funder
National Health and Medical Research Council
Funding Amount
$445,270.00
Summary
The ultimate fate of most of our cells is to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs ....The ultimate fate of most of our cells is to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs that are used to treat cancer may exert their effect by inducing apoptosis, a failure of this suicide response may cause resistance to chemotherapy. The genes of the apoptosis pathway function either to promote or inhibit cell death. We have found that some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die. If these genes are mutated then apoptosis does not occur and a functional cell may survive. The distinction between cells that decide fate and those that do not is crucial because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We use a model in which apoptosis is caused by removal of a growth factor, using cell lines derived from mice that lack particular genes in the cell death pathway. These cells proliferate normally in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Because these cells are sensitive to chemotherapeutic drugs, we can also determine the contribution these genes make to cancer drug sensitivity. Using this system, we have discovered that Puma, a gene known to be required for apoptosis in response to radiation, is also a critical activator of apoptosis following growth factor withdrawal. We will determine the manner in which Puma is regulated by growth factors, as well as identify and characterise other key components.Read moreRead less
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.
Using The A33 Antigen Gene Locus To Generate Novel Mouse Models Of Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising ....Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising progressively and sharply from age 50 onwards. Like all cancers, colorectal cancer results from the progressive acquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to colorectal cancer accumulate in the epithelial cells that provide the lining to the bowel. The progression of colorectal cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as APC, beta-catenin, Kirsten-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. Moreover, some of the mutations are highly associated with distinct stages of colon tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) colorectal cancer. In our proposal, we are aiming to establish colorectal cancer in mice. Our approach will be to progressively introduce mutant genes into intestinal epithelial cells (singly and in combination) and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the intestines of mice. This will help us to understand which mutant genes are required for each stage in tumour development and may provide more rational approaches to bowel cancer screening and treatment.Read moreRead less