Pathogenesis Of Infections With Yersinia Enterocolitica
Funder
National Health and Medical Research Council
Funding Amount
$339,634.00
Summary
Yersinia enterocolitica is a significant cause of food-poisoning, gastroenteritis and abdominal pain which may be mistaken for acute appendicitis. Y. enterocolitica is a heterogenous bacterial species only some strains of which are able to cause disease. Many of the disease-causing strains have readily identifiable virulence determinants which facilitate their detection in clinical microbiological laboratories. By contrast, other types, in particular the biotype 1A strains, lack these determinan ....Yersinia enterocolitica is a significant cause of food-poisoning, gastroenteritis and abdominal pain which may be mistaken for acute appendicitis. Y. enterocolitica is a heterogenous bacterial species only some strains of which are able to cause disease. Many of the disease-causing strains have readily identifiable virulence determinants which facilitate their detection in clinical microbiological laboratories. By contrast, other types, in particular the biotype 1A strains, lack these determinants, although many of them are significantly associated with disease. During the past few years, we have compared biotype 1A strains of Y. enterocolitica obtained from patients with those from non-clinical sources in a number of assays for virulence-associated properties. These studies have shown that clinical isolates differ from non-clinical ones in terms of their ability to (1) invade epithelial cells in vitro and intestinal absorptive cells in vivo, (2) escape from epithelial cells and macrophages they have invaded, (3) resist killing by macrophages, and (4) colonise the intestinal tracts of mice. The aim of the study is to identify the bacterial determinants responsible for these differences between clinical and non-clinical strains of Y. enterocolitica biotype 1A. This will be achieved by using genetic techniques to modify virulent strains of biotype 1A at random and then identify derivatives of these bacteria with altered virulence properties. We shall also use genetic techniques to identify genes that are specifically activated when the bacteria come into contact with animal cells and tissues. The results of this research will provide new insights into the virulence mechanisms of Y. enterocolitica and related bacteria, and will be used to develop diagnostic tests which will allow pathogenic strains to be distinguished from harmless ones.Read moreRead less
The pneumococcus is a major cause of bacterial pneumonia, sepsis and meningitis especially in children and the elderly. Antibiotic-resistant pneumococci are becoming more prevalent, and available vaccines have major shortcomings. We propose to identify and characterise the factors produced by this organism during infection that enable it to cause invasive disease. Such factors could be incorporated into protein-based pneumococcal vaccines currently under development.
Electric Field Manipulation For Targeted Neural Excitation
Funder
National Health and Medical Research Council
Funding Amount
$545,135.00
Summary
The aim of this study is to investigate innovative techniques for steering current to enhance existing and assist in the development of new neurostimulation strategies.
Immunotherapy has recently shown promise in bone cancer. We have found that while immune modulators Il-6 and Ifn?? contribute to tumour suppression Il-23 promotes the growth of radiation-induced bone cancer. We have generated mouse models of bone cancer to investigate tumour growth and immune surveillance in immune competent mice with an overall aim of identifying therapeutic targets in this disease.
Combinatorial Therapeutics In High-risk Infant Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$340,891.00
Summary
Modern therapies for children with leukaemia are curative in more than 90%. In contrast, survival for infants less than one year of age at the time of diagnosis is less than 50%. Better therapies are desperately needed. From laboratory testing we have discovered effective novel cancer drugs, which are not currently used for treatment of babies with leukaemia. We will evaluate novel drug combinations and test them in model systems, such that they can be fast-tracked to the clinic.
Dissecting In Vivo Cellular Responses To Interferons In Pathogen-infected Hosts
Funder
National Health and Medical Research Council
Funding Amount
$479,694.00
Summary
Tuberculosis (TB) is caused by virulent bacterium Mycobacterium tuberculosis and is a leading cause of death worldwide. Mechanisms underlying host resistance to the pathogen are poorly understood. Using a novel reporter mouse, the function of interferons in Mtb infection will be defined in vivo by tracking the cytokine-responsive cells. This will increase our understanding of the effects of these important cytokines in vivo, and could provide new candidate biomarkers for TB diagnosis.
Role Of Impaired Insulin Signalling In Fatty Acid-induced Muscle Insulin Resistance In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contr ....Type 2 diabetes represents an escalating global health problem. In Australia 7.5% of the population has diabetes and another 16% insulin resistance (impaired action of insulin in tissues). As well as diabetes, insulin resistance is closely associated with obesity, dyslipidaemia, hypertension and cardiovascular diseases (Syndrome X). While genetic factors play a role, a high caloric intake (particularly with a high fat content) and a sedentary lifestyle are extremely important environmental contributors to Syndrome X and diabetes. From evidence that we and others have obtained over the last few years it is now evident that an important mediator of insulin resistance is the quantity of fat molecules which accumulate in muscle and liver. This project examines mechanisms whereby this fat accumulation can disrupt the signalling mechanism normally causing increased glucose metabolism in response to insulin. While basic experiments in cell systems have identified some candidates, a need exists to demonstrate whether they actually cause the insulin resistance in the whole animal or human, or are merely associated with it. We will combine metabolic-physiological studies with a novel technique we have recently established in our laboratory for introducing DNA into skeletal muscle of laboratory animal models. We now aim to exploit this approach to obtain more definitive data about the importance of insulin signalling changes to insulin resistance. Two major steps in insulin signalling will be investigated, involving the insulin receptor substrate proteins and the kinase Akt-PKB, both strongly implicated in lipid-induced insulin resistance. This knowledge will be invaluable in improving strategies to lessen or prevent lipid-associated insulin resistance, a major contributor to the metabolic derangement in Type 2 diabetes and Syndrome X.Read moreRead less
Neutrophil-macrophage Co-operation In The Resolution Of Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$325,854.00
Summary
Failed inflammation resolution is at the core of many diseases and has a significant impact on the progression of cancers and atherosclerosis. Visualising and manipulating inflammation in zebrafish has led to key discoveries. Neutrophil-macrophage interactions may be a key process regulating inflammation resolution, and understanding this process better at a molecular level is likely to identify important pathways that might be manipulated for the benefit of patients with chronic inflammation.