Role Of Obesity In Impaired Treatment Response In Chronic Hepatitis C: Mechanisms And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
The overall objective of this Research Project is to examine the mechanisms by which obesity and fatty liver impair the response to antiviral treatment in patients with chronic hepatitis C and to develop specific strategies to monitor and improve the outcome of treatment. In addition, the development of non-invasive strategies and surrogate cell culture systems for the assessment and serial monitoring of the antiviral response will be of substantial benefit.
HPV And Cervical Carcinoma: Signaling And Clinical Responses To Interferons
Funder
National Health and Medical Research Council
Funding Amount
$534,480.00
Summary
Cervical carcinoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers caused by the wart virus. However, results of recent work indicates that viruses like the wart virus, HPV, have developed ways of inhibiting its eff ....Cervical carcinoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers caused by the wart virus. However, results of recent work indicates that viruses like the wart virus, HPV, have developed ways of inhibiting its effectiveness. We have found that cervical carcinoma cells and virally infected cells resist the direct anti-cancer and anti-viral effects of interferons because they have abnormalities in their ability to respond to interferon. We have made good progress in understanding why these cells do not respond to the interferons. In particular they show a deficiency in the activity of cell proteins required to transmit the interferon signal inside the cells. The current proposal will allow us to gain a greater understanding of the processes inside cells that are taken over by the wart viral proteins and the reasons for its abnormality in interferon resistant cancer cells. We will determine whether the levels of certain genes in clinical samples from patients relates to their response to interferon treatment. This may allow us to establish a test to predict which patients will respond to interferon therapy, saving patients from ineffective treatment, side effects and cost. This study will have a broad significance to many human diseases where abnormalities in interferon signaling occur and will help to bring about the necessary changes in cell properties to overcome the abnormalities, restore the responses and improve the application of interferons to treat infectious diseases and perhaps other cancers as well.Read moreRead less
Regulation Of Stat1 Activity Levels: Abnormalities In Human Melanoma Cells Resistant To Interferon.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Melanoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers like malignant melanoma. However, results of recent trials have cast doubt on its effectiveness. We have found that advanced stage melanoma cells resist the d ....Melanoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers like malignant melanoma. However, results of recent trials have cast doubt on its effectiveness. We have found that advanced stage melanoma cells resist the direct anti-cancer effects of interferons because they have abnormalities in their ability to respond to interferon. We have made good progress in understanding why the melanoma cells do not respond to the interferons. In particular they show a deficiency in the activity of protein, Stat1, required to send the interferon signal inside the cells. The current proposal will allow us to gain a greater understanding of the processes inside cancer cells regulating Stat1 activity and the reasons for its abnormality in interferon resistant cancer cells. This study will help establish an assay to predict which cancer patients will respond to interferon therapy, saving pateints from unecessary discomfort and costs. It will also have a broad significance to many human diseases where abnormalities in interferon signaling occur and will help to bring about ways to produce the necessary changes in cell properties to overcome the abnormalites, restore the responses and improve the application of interferons to treat melanoma and perhaps other human diseases as well.Read moreRead less
New Mechanisms Of Immunomodulation By Interferon Transsignaling
Funder
National Health and Medical Research Council
Funding Amount
$540,441.00
Summary
The aim of this project is to characterise a new discovery of how the body can regulate its response to disease such as infections and cancer. Interferons are produced by the body to stimulate immune reactions to these diseases. We have dicovered that a circulating form of an interferon binding protein or receptor can change the nature of an immune response. We plan to study how this is achieved and whether this information can be used therapeutically.
I work on the molecular mechanisms of innate immunity. Priorities of my work are the immune response to pathogens such as viruses and bacteria and to cancer.
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
Type I Interferon Signalling In Bacterial Infection
Funder
National Health and Medical Research Council
Funding Amount
$738,274.00
Summary
Infectious diseases are a leading cause of death in Australia. Activation of disease-fighting inflammasomes sets in motion rapid immune defenses against pathogens. In this project, we explore how cell-cell communication molecules known as type I interferons communicate with inflammasomes to achieve the best outcome in the body in response to deadly bacterial infection. Understanding how these signals communicate with one another could reveal new ways to fight infectious diseases.
Understanding Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,043,216.00
Summary
This project opens a new line of enquiry into the cellular signalling mechanisms involved in the progression of AD and establishes whether targeting the involvement of type-1 IFN signalling influences the evolution of AD. New and novel approaches are clearly required to treat AD. Importantly, we believe that neuroinflammation is common to all causes of dementia and targeting the neuroinflammatory pathways has much wider implications than targeting the primary causative pathway.
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