Genetic Dissection Of The Gp130 Signalling Network; Implications In The Initiation Of Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$447,500.00
Summary
Stomach cancer is a major health problem in the world. It is the second most common cancer and the second leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers, stomach cancer results from the progressive acquisition of mutations in ....Stomach cancer is a major health problem in the world. It is the second most common cancer and the second leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers, stomach 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 stomach cancer accumulate in the epithelial cells that provide the lining to the stomach. The progression of stomach cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as Kirsten-ras, p53) are commonly found in stomach tumours. Moreover, some of the mutations are highly associated with distinct stages of tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) stomach cancer. In our proposal, we are aiming to establish stomach cancer in mice. Our approach will be to use an existing animal model which is predisposed to stomach cancer. We will progressively introduce mutant genes into stomach epithelial cells and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the stomach 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 stomac cancer screening and treatment.Read moreRead less
Elucidating The Molecular Regulation Of Gp130 Complex Signalling In Lipid And Glucose Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Overnutrition promotes obesity, which greatly increases the risk of type 2 diabetes and cardiovascular disease. We have provided evidence that activation of gp130 signalling may enhance insulin action and fatty acid oxidation in metabolically active tissues. My research proposal aims to elucidate the molecular regulation of gp130 complex signalling in lipid and glucose metabolism in important metabolic tissues.
Loss Of Cytostatic Regulation By TGF-beta During EGFR-driven Tumor Development
Funder
National Health and Medical Research Council
Funding Amount
$605,031.00
Summary
Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulato ....Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulators in tumour formation and as such they are potential therapeutic targets. However, while both pathways have been studied extensively, little is known about the cross-talk between the TGF-b and EGF pathways. This project will establish the generality of a new tumor signaling axis, namely EGFR-Stat3-Smad7-TGF-b in EGFR-overexpressing tumors. Practically, it will provide guidelines for the development of new approaches for treating effectively the EGFR-driven tumors.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
Characterization Of HLS5, A Novel Tumor Suppressor Gene
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 ....HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 is a tumour suppressor gene comes from the proteins it associates with these partner molecules are involved in DNA repair or DNA regulation. When we introduced HLS5 into cancer cells, it slowed their growth and reduced their ability to form tumours. The aim of this project therefore, is to undertake a detailed analyses of the HLS5 gene and to determine the function of its protein product. A combination of approaches will be used in this study. We will: (i) alter the amount of HLS5 expression in cancer cells, (ii) characterize the proteins which bind to HLS5, (iii) determining where HLS5 localizes in the cell, (iv) analyze mice with lack the gene for HLS5, (v) assess the involvement of HLS5 in a human leukemia (vi) analyze HLS5 messenger RNA which produces the protein, and (vii) determining the structure of HLS5 protein. These studies should provide valuable information on how HLS5 functions, as well as its role in cancer formation.Read moreRead less
Apoptosis is a fundamental mechanism in regulating normal development and preventing cancer. Cancer cells must avoid apoptosis and also adapt to harsh metabolic environments in order to survive in the absence of effective nutrient supply and to resist the action of certain drugs. This project will provide a detailed analysis of metabolic changes allowing cells to survive long periods when the apoptotic process is absent and nutrients are limiting.