Understanding The Function Of The CCR7 Chemokine Receptor In Breast Cancer Cells And Tumours.
Funder
National Health and Medical Research Council
Funding Amount
$549,446.00
Summary
As much as 90% of cancer related deaths occur due to the development of metastatic tumours, and to be able to develop efficient therapies for malignant cancers it is necessary to uncover and study in detail the specific characteristics that allow cancer cells to disseminate from the site of primary tumour. Recent work has implicated proteins that regulate cell movment known as chemokines in this process. We wish to identify and understand the mechanisms by which breast cancer cells use chemokine ....As much as 90% of cancer related deaths occur due to the development of metastatic tumours, and to be able to develop efficient therapies for malignant cancers it is necessary to uncover and study in detail the specific characteristics that allow cancer cells to disseminate from the site of primary tumour. Recent work has implicated proteins that regulate cell movment known as chemokines in this process. We wish to identify and understand the mechanisms by which breast cancer cells use chemokines and their receptors, molecules normally employed by blood cells, to promote tumour metastasis to specific anatomical sites with a view to identify novel targets for therapeutic intervention and risk assessment in breast cancerRead moreRead less
The Role Of SPARC In Intestinal Extracellular Matrix Changes And Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$526,728.00
Summary
The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer ....The inflammatory bowel diseases (IBDs), Crohn s disease (CD) and ulcerative colitis (UC), are lifelong, chronic, incurable conditions and the number of patients being diagnosed with these conditions is increasing worldwide. Over recent years there has been the development of new treatments effective in controlling the chronic inflammation of the bowel in many of these patients. There is no evidence, however that these therapies reduce the rate of bowel scarring or the development of bowel cancer that complicated these conditions. Healing of the bowel inflammation can result in scarring. Whether scarring develops or not hinges on the balance between tissue production and destruction. If production outstrips destruction then scarring may occur, but if this balance can be modified in favour of reduced production then, potentially, healing may proceed without scarring. This project aims to investigate the role of a protein, SPARC, that can regulate scar formation and its interactions with other proteins that can alter scar formation in a mouse model of chronic bowel inflammation. Chronic inflammation of the bowel can also cause the development of colon cancer. Colon cancer is one of the most common cancers in the Australian population. The level of SPARC in the colon cancer at time of initial surgery may predict the risk of disease recurrence. The aim of this study is to determine if SPARC levels can identify those patients at higher risk of cancer recurrence. The role of SPARC will also be examined in a mouse model of colon cancer to determine if increased SPARC levels increased or decrease the rate of cancer growth and its spread.Read moreRead less
THE ROLE OF RESIDENT MAST CELLS IN ISCHAEMIA-REPERFUSION INJURY OF SKELETAL MUSCLE.
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
NHMRC 209113 LAY DESCRIPTION Ischaemia reperfusion injury occurs in skeletal muscle when the blood-oxygen supply is cut off (ischaemia) and later restored (reperfusion). If the duration of ischaemia is short some of the muscle survives. However, when blood flow and oxygen are restored the muscle is subjected to more injury, which is thought to be caused by oxygen and-or white blood cells. This type of injury occurs in muscle which has been crushed, limbs that have been broken or traumatized, in ....NHMRC 209113 LAY DESCRIPTION Ischaemia reperfusion injury occurs in skeletal muscle when the blood-oxygen supply is cut off (ischaemia) and later restored (reperfusion). If the duration of ischaemia is short some of the muscle survives. However, when blood flow and oxygen are restored the muscle is subjected to more injury, which is thought to be caused by oxygen and-or white blood cells. This type of injury occurs in muscle which has been crushed, limbs that have been broken or traumatized, in replantation of amputated parts, in transplantation, after some surgical procedures and after microsurgical transfer of muscle. Once established there is no effective treatment. Our experiments show that a particular cell, the mast cell, and a particular molecule, nitric oxide, are involved in causing ischaemia reperfusion injury. However, the extent of their involvement is unknown. In this proposal we will investigate the effect of replacing mast cells into muscles, in a unique variety of mice which normally don t contain mast cells and are resistant to ischaemia reperfusion injury. In one group of mice we will put back normal mast cells and in a second group of mice we will put back mast cells that cannot produce the nitric oxide molecule. These experiments will determine, unambiguously, the extent of involvement of mast cells and mast cell-derived nitric oxide. In the second part of this proposal will carry out a time course study, using pharmacologically induced mast cell degranulation, to determine when the mast cells become injurious to skeletal muscle. These experiments will identify the period during which mast cell behaviour can be modulated in order to protect the muscle from ischaemia reperfusion injury. Determination of the role of mast cells, and an understanding of the timing during which they become injurious would provide a logical basis for optimizing drug therapy in clinical applications of these findings.Read moreRead less
A Study Of The Molecular Pathogenesis Of Murray Valley Encephalitis Virus In Mice Using Infectious Clone-derived Virus
Funder
National Health and Medical Research Council
Funding Amount
$194,595.00
Summary
The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impo ....The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impose a considerable burden on affected individuals and on community health and rehabilitation services. Currently there are no effective treatments, other than supportive measures, available for acute flavivirus encephalitis. The research outlined in this grant application is designed to understand the complex interaction between a pathogenic virus and it's mammalian host at the molecular, cellular and whole animal level. To achieve this aim, we have developed an infectious cDNA clone of Murray Valley encephalitis virus, allowing us to create genetically defined attenuated viruses containing single or limited amino acid differences from the virulent wild-type virus. This research will allow us to achieve a comprehensive understanding of how single or limited nucleotide changes in the genomes of laboratory-derived mutants result in attenuation of virulence in a mammalian host . This research has important implications for the development of genetically defined, live-attenuated flavivirus vaccines engineered from infectious cDNA clones. We have recently shown that the pathogenesis of Murray Valley encephalitis in mice results, in part, from host inflammatory responses. Thus, we plan to rigorously analyze the inflammatory responses to MVE infection in mice and to assess the ability of several anti-inflammatory agents to alleviate the clinical manifestations of acute Murray Valley encephalitis or it's neurological sequelae in mice.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
The Contribution Of Gp130-Stat3 During Wnt-beta-catenin Induced Intestinal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$396,275.00
Summary
There is growing evidence that cancer is initiated and develops not by the deregulation of a single gene or signaling pathway, but by multiple events. We will study the co-operation between two pathways - gp130-Stat and Wnt. These signaling pathways are frequently deregulated in many types of cancer, however their interaction remains poorly understood. We shall explore their mechanism of interaction during intestinal cancer in order to develop a novel therapeutic target for this disease.
Functional Analysis Of The Ym2 Chitinase-like Lectin In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response tha ....The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response that is biased toward production of allergy-related T helper 2 cytokines of which interleukin (IL)-13 is a potent mediator of disease. However, the molecular processes linking IL-13 with abnormal airway wall changes are unclear. To identify previously uncharacterised IL-13-related molecules, we used a protein profiling approach that identified a novel lectin (carbohydrate-binding protein) termed Ym2, which is secreted abundantly into the airway fluid of mice in which allergic airways disease has been induced. Preliminary studies suggest that Ym2 is an intermediary of IL-13 that is involved in respiratory dysfunction. This project aims to work out how Ym2 interacts with the molecules and cells of the respiratory tract to regulate allergic disease. Specific inhibitors of Ym2 will be developed to examine what happens to allergic responses when Ym2 can t function; transgenic mice will be developed to determine if we see features of allergy when Ym2 is over-expressed in the normal lung, and human samples will be screened to identify the human counterpart of Ym2 and whether this counterpart is secreted into the lung fluid of asthmatics. Defining the mechanism by which Ym2 regulates the pathogenesis of allergic disease will not only contribute to our basic understanding of the processes underlying asthma pathology, but also generate new information for better design of therapeutics directed against specific mediators of this debilitating and widespread disease.Read moreRead less
Phenotypic Studies Of The NaSi-1 Transporter Knock-out Mouse
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by re ....Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by regulating kidney reabsorption. Normally, very little sulfate is lost in the urine. However, individuals with autism, Alzheimers, Parkinsons, motor neurone disease and liver cirrhosis, have been reported to have reduced blood sulfate levels. The mechanisms underlying the low blood sulfate levels in these disorders, have not been characterised. Recently, we generated a mouse lacking the Nas1 gene. This mouse has very low blood sulfate levels and suffers from growth retardation, reduced fertility and displays seizures. In this study, we plan to investigate these phenomena in the Nas1 knock out mouse and determine the role of low blood sulfate levels on these conditions. We also plan to characterise the role of low blood sulfate levels on the expression of genes in various body organs, using a gene array approach. In addition, we plan to study wound repair and the detoxification process in our Nas1 knock out mouse, which we expect to be affected due to low blood sulfate levels. These studies will establish the roles sulfate plays in mammalian physiology and will provide a foundation for studying diseases that are associated with changes in blood sulfate levels.Read moreRead less