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
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
I will determine the efficacy and safety of crystalloid resuscitation fluids in conventional models of care. This is a fundamental and unresolved question in Intensive Care Medicine and will have an impact on clinical practice worldwide. I will also consolidate and enhance a series of projects to provide the next generation of clinician-researchers with high-quality research opportunities. These include projects in sepsis, traumatic brain injury, and endocrine function in critical illness.
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.
Despite advances in medical management, critical care clinicians continue to search for procedures that will improve outcomes in critically ill patients with haemorrhagic shock (a life-threatening fall in blood pressure). Shock is a consequence of an active process triggered by the brain . The proposed research aims to elucidate the precise sequence of brain events that initiate and maintain shock. We will also evaluate the effects of interventions (designed to ameliorate or reverse shock) on th ....Despite advances in medical management, critical care clinicians continue to search for procedures that will improve outcomes in critically ill patients with haemorrhagic shock (a life-threatening fall in blood pressure). Shock is a consequence of an active process triggered by the brain . The proposed research aims to elucidate the precise sequence of brain events that initiate and maintain shock. We will also evaluate the effects of interventions (designed to ameliorate or reverse shock) on the brain events that drive the shock response. The results of this research will offer, for the first time, a rational basis for devising new methods to reverse or ameliorate shock and potentially improve clinical outcomesRead moreRead less
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.
Counteracting Age-associated Neurodegenerative Diseases Using Chaperone-based Amyloid Disaggregases
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
In neurodegenerative diseases such as Alzheimer’s disease, proteins form clumps through changes in structure due to mutations or proteotoxic chemical insults. The formation of these toxic clumps causes brain cells to die prematurely triggering symptoms such as dementia. I have identified a molecular machine in human cells that efficiently clears these clumps. We are now developing strategies to activate this machine to repair damaged brain cells to slow/reserve neurodegenerative diseases.
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.