Self Adjuvanting CTL-Based Influenza Vaccines For Human Use
Funder
National Health and Medical Research Council
Funding Amount
$214,842.00
Summary
This project will generate novel vaccines that elicit cell-mediated immunity against influenza infection. The vaccines are totally synthetic and therefore not constrained by the limitations in manufacturing which currently confront egg-grown vaccines. These vaccines induce very strong immune responses because they target dendritic cells which are pivotal for induction of all immune responses. This targeting capability is due to a simple lipid molecule incorporated into the vaccine which is recog ....This project will generate novel vaccines that elicit cell-mediated immunity against influenza infection. The vaccines are totally synthetic and therefore not constrained by the limitations in manufacturing which currently confront egg-grown vaccines. These vaccines induce very strong immune responses because they target dendritic cells which are pivotal for induction of all immune responses. This targeting capability is due to a simple lipid molecule incorporated into the vaccine which is recognised by specific receptors on the surface of dendritic cells and also causes their maturation, a step which is essential for recognition by the immune system of potential pathogens. The technology to design and assemble these new vaccines is already.Read moreRead less
Loss of insulin-producing beta cells leads to type 1 diabetes and rejection of allogeneic islet transplants. The aim of this program is to discover ways of protecting beta cells from damage. We will do this by investigating whether blocking crucial regulators of cell death can protect mouse and human beta cells from destruction in vitro and in vivo. In doing so, we aim to prevent diabetes in mice and potentially improve the survival of islet grafts after transplantation.
Roles Of Enzymes Of The Dipeptidyl Peptidase Gene Family In Human Liver
Funder
National Health and Medical Research Council
Funding Amount
$79,750.00
Summary
Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infe ....Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infections will progress to liver failure or liver cancer within 30 years. Diabetes afflicts 150 million people, and 90% have Type 2 diabetes. We request funding of our research on a family of enzymes highly prospective as targets for novel therapies for these diseases. We are internationally recognised experts on this enzyme family and on liver disease. The prototype member of this enzyme family, dipeptidyl peptidase (DP) IV, is being targeted by novel drugs that are in phase III clinical trials for Type 2 diabetes. Family member fibroblast activation protein (FAP) is targeted by novel anti-cancer drugs We were first to clone and lodge patent applications for two new enzymes of this family, DP8 and DP9. Our research proposal would lead to determination of whether FAP, DP8 and-or DP9 are valuable targets for novel liver disease therapeutics and facilitate generating the development of such therapeutics by a more thorough understanding of the activities and roles of these enzymes Completion of this project will greatly increase our understanding of these enzymes and their roles in chronic liver injury. This work can potentially lead to the development of specific inhibitors of enzyme function designed to relieve liver damage.Read moreRead less
Gamma-ray Inactivated Influenza A Virus Vaccine For Cross-protective T Cell Immunity
Funder
National Health and Medical Research Council
Funding Amount
$239,963.00
Summary
Although there are new antiviral drugs that appear to be effective against influenza virus, the far more costeffective and efficient means to combat an influenza pandemic would be by vaccination. Current influenza vaccines employ virus preparations that are inactivated by chemical treatment. The inactivated vaccines, which function mostly by inducing antibody against the virus, have to be reformulated almost every year to take account of the changing virus because the antibodies recognize the vi ....Although there are new antiviral drugs that appear to be effective against influenza virus, the far more costeffective and efficient means to combat an influenza pandemic would be by vaccination. Current influenza vaccines employ virus preparations that are inactivated by chemical treatment. The inactivated vaccines, which function mostly by inducing antibody against the virus, have to be reformulated almost every year to take account of the changing virus because the antibodies recognize the viral surface which is prone to mutation. Accordingly, in terms of the threatening H5N1 avian influenza pandemic, it is not known if an inactivated vaccine based on the circulating H5N1 strain will be effective if the virus mutates to adapt to efficient growth and spread in the human population. In contrast to the antibody response against influenza virus, the cytotoxic T cell response is broadly crossreactive between heterologous influenza virus strains. Live virus infection efficiently induces cytotoxic T cell immunity which plays an important role in reducing disease severity and mortality following infection with a second, heterologous influenza virus, although infection per se is not prevented. Accordingly, vaccination strategies that elicit cytotoxic T cell memory should be given urgent consideration in the preparation against an influenza pandemic. We have found that the use of gamma-irradiation (in contrast to chemical treatment) for the preparation of inactivated experimental vaccines against influenza and other viruses does not destroy the ability of the vaccines to elicit cytotoxic T cell immunity. The gamma-ray inactivated vaccines conferred protection against lethal challenge with heterologous influenza virus strains in mice. This proposal is aimed at extending this novel finding to avian influenza viruses and to uncover the mechanisms involved in the cytotoxic T cell immunogenicity of gamma-ray inactivated vaccines.Read moreRead less
THE DETECTION AND MANAGEMENT OF DEMENTIA IN GENERAL PRACTICE.
Funder
National Health and Medical Research Council
Funding Amount
$499,977.00
Summary
This research aims to examine a new method and practice guidelines for detection of early dementia. General practitioners will be screened on their ability to diagnose and manage dementia and to distinguish it from other diseases. Patient outcomes - including quality of life, depression, and satisfaction with care and referral indicators - will be examined.
Cognitive Outcome And Therapeutic Interventions For Coronary Artery Disease.
Funder
National Health and Medical Research Council
Funding Amount
$392,104.00
Summary
Dementia is recognized as an increasingly important factor affecting quality of life as people age. Deaths from heart disease are declining, in part due to improved surgical techniques and to the use of less invasive methods to keep arteries open such as coronary stenting. It is now well known that 20 to 60% of patients experience some degree of impairment in thinking ability (cognitive impairment) after cardiac surgery, that this will persist in some of these individuals for years and may incre ....Dementia is recognized as an increasingly important factor affecting quality of life as people age. Deaths from heart disease are declining, in part due to improved surgical techniques and to the use of less invasive methods to keep arteries open such as coronary stenting. It is now well known that 20 to 60% of patients experience some degree of impairment in thinking ability (cognitive impairment) after cardiac surgery, that this will persist in some of these individuals for years and may increase the risk of long-term problems. Cognitive impairment affects people in many ways. While it is not yet known whether the occurrence of cognitive impairment predisposes to dementia, it is thought that Mild Cognitive Impairment (MCI) may do so. We propose to explore the link between MCI and Post Procedural Cognitive Deficit (PPCD) in patients with coronary disease from before the first point of objective diagnosis, i.e. prior to the coronary angiogram, and over a 12-month period, through and subsequent to further treatment interventions such as stenting or cardiac surgery. Our Pilot data suggest that PPCD does indeed occur after angiography, and we propose to identify how long this lasts, whether MCI predisposes to it and whether it is better to wait until it resolves before further interventions are undertaken. In this way we hope to identify the safest treatment strategy for patients with coronary disease that will minimize the occurrence of Cognitive Deficit and possibly longer-term cognitive changes after investigation and treatment for their symptoms.Read moreRead less
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune syste ....In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.Read moreRead less
They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid ....They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.Read moreRead less