The Opposing Roles Of STAT1 And STAT3 Signalling By IL-6 Family Cytokines In Inflammation And Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
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 for a receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and peritonitis, two chronic inflammatory disorders induced by bacterial ....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 for a receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and peritonitis, two chronic inflammatory disorders induced by bacterial infection. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of epithelial cells that line the stomach wall, as well as uncontrolled regulation of the immune system leading to local and systemic inflammation. At the molecular level, the mutation in gp130 leads to over-activation of two signalling molecules, Stat1 and Stat3, which are also used by a range of other receptors to transmit specific cellular responses. In the context of cancer and inflammation, Stat1 and Stat3 have opposing roles (ie Stat3 promotes cancer and can be both anti-pro-inflammatory, while Stat1 suppresses cancer and is pro-inflammatory), although as yet, the contribution of the gp130 receptor in directing Stat1 and Stat3 activation in these disorders is not known. Our proposal employs established strategies and unique mouse models to specifically address how the mutation in gp130 can orchestrate the opposing biological functions of these two molecules to drive stomach cancer and inflammation. The identification of mechanisms by which gp130-dependent activation of these two molecules causally relate to inflammation and stomach cancer will ultimately provide novel and rational approaches to target these molecules for the screening and treatment of various inflammatory disorders and cancers, including those of the stomach.Read moreRead less
Delineating The Role Of Fludrocortisone And Hydrocortisone In The Management Of Patients With Septic Shock
Funder
National Health and Medical Research Council
Funding Amount
$553,664.00
Summary
Sepsis and septic shock are leading causes of morbidity and mortality globally. Steroids have been used to treat septic shock for decades. Two new trials, one using hydrocortisone vs. placebo and another using hydrocortisone plus fludrocortisone vs. placebo have produced differing results, with fludrocortisone possibly conferring a mortality benefit. My Program will investigate this evidence gap by providing critical evidence for the design and execution of a future definitive trial.
Sepsis is a major cause of hospitalization and ICU admission in Australia population corresponding to more than 15700 new cases each year. Every year more than 3000 people die from sepsis in Australia which is greater than the annual national road toll and breast, prostate or colorectal cancer. The research outlined in this proposal to study the effect of steroids and vitamin D to improve patient’s recovery from sepsis and also understand the genetic basis behind their ability to survive sepsis.
Therapeutic Potential Of Inhibiting Eph/ephrin Signalling To Repair The Vascular Endothelium In Septic Shock
Funder
National Health and Medical Research Council
Funding Amount
$664,734.00
Summary
Septic shock is a life-threatening condition usually caused by bacterial infection in the bloodstream. More than 5000 people, including 500 children, die from sepsis each year in Australia. Worldwide, it is the most significant cause of death in children. Sepsis is associated with leakage of fluid and proteins through the cells lining the blood vessels. This project will develop and test a novel treatment for sepsis which focuses on reducing this leakage by blocking the Eph/ephrin proteins.
The Role Of Apoptosis In Pathogenesis And Immunology Of Salmonella Infections
Funder
National Health and Medical Research Council
Funding Amount
$276,988.00
Summary
Salmonellae are important human pathogens in developed and developing countries. The most severe salmonella disease, typhoid fever, is becoming more difficult to treat because of increasing antibiotic resistance. In addition, current vaccines only provide short-term protection. The studies in this proposal are designed to answer important questions about immunity against typhoid fever, including how this immunity is provoked, and the direct and indirect causes of pathology in the disease. The fo ....Salmonellae are important human pathogens in developed and developing countries. The most severe salmonella disease, typhoid fever, is becoming more difficult to treat because of increasing antibiotic resistance. In addition, current vaccines only provide short-term protection. The studies in this proposal are designed to answer important questions about immunity against typhoid fever, including how this immunity is provoked, and the direct and indirect causes of pathology in the disease. The focus of this project is the induction of host cell apoptosis, an important virulence mechanism shared by many bacteria and viruses. The research will have direct application to human typhoid and may lead to novel therapies and improved vaccines for typhoid fever.Read moreRead less
Gene Expression Profiling In Critically Ill Patients With Septic Shock: The ADRENAL-GEPS Study
Funder
National Health and Medical Research Council
Funding Amount
$863,304.00
Summary
Sepsis refers to a whole body inflammation caused by severe infection. Approximately one in three adults admitted with septic shock die within 28 days and it is unclear whether treatment with anti-inflammatory drugs is beneficial in terms of patient survival. The aim of this study is to develop a clinical test based on gene activity that can be used to predict patient survival and also determine what the best treatment might be for individual patients.
Septic shock is a common clinical problem; it is frequently associated with kidney failure that increases mortality. We aim to determine the changes within the kidney that cause it to fail. We will establish whether oxygen levels and blood flow are altered within the kidney, and if blood is shunted through specific blood vessels, reducing flow in critical areas. Importantly, we will determine if clinical treatments used to improve kidney function cause long-term damage by reducing tissue oxygen.
A Multi Centre, Randomised, Blinded, Placebo Controlled Trial Comparing Intravenous Hydrocortisone With Placebo In Critically Ill Patients With Septic Shock.
Funder
National Health and Medical Research Council
Funding Amount
$317,997.00
Summary
This study performed across Australia and New Zealand will evaluate whether hydrocortisone, a cheap drug when administered to critically ill patients with severe infection, will save lives.