Cholera Toxin Co-receptor Interaction In The Prevention Of Inflammatory Autoimmune Disorders
Funder
National Health and Medical Research Council
Funding Amount
$359,577.00
Summary
Vaccination is undoubtedly one of mankind's greatest achievements. While infections continue to be the major cause of morbidity and mortality in the developing world, heart disease, cancer, chronic allergies and autoimmune disorders are taking their toll in advanced societies. Our expanding knowledge of these 'modern diseases' shows that the immune system plays a central role and hence it is important to learn if new immunologically-based therapies can be developed for such chronic human disorde ....Vaccination is undoubtedly one of mankind's greatest achievements. While infections continue to be the major cause of morbidity and mortality in the developing world, heart disease, cancer, chronic allergies and autoimmune disorders are taking their toll in advanced societies. Our expanding knowledge of these 'modern diseases' shows that the immune system plays a central role and hence it is important to learn if new immunologically-based therapies can be developed for such chronic human disorders. This project takes advantage of our recent discoveries on the immunological properties of a hitherto feared molecule - cholera toxin. We have shown that one portion of the toxin, the B-subunit, responsible for binding to cell membranes, possesses remarkable immunomodulatory properties that prevent the development of inflammatory autoimmune disorders such as rheumatoid arthritis in animal models. The B-subunit, in contrast to the whole cholera toxin, is non-toxic and has no adverse effects in humans. This has sparked considerable interest in the development of such molecules as novel anti-inflammatory agents and highlighted the necessity to better understand the B-subunit's mode of action. Current theory specifies that the B-subunit mediates its immunomodulatory effects by binding and cross-linking a ubiquitous plasma membrane glycosphingolipid, GM1 ganglioside. The essential role of GM1-interaction was recently challenged by our discovery that a mutant B-subunit (H57A) was unable to modulate the immune system even though it still bound to GM1; suggesting that the B-subunits interact with another receptor (or co-receptor), and that it is this second interaction that directs the immune system to prevent development of autoimmune disease. The primary aims are to characterize the nature of B-subunit interaction with the cell membrane and to identify the co-receptor. This work has the potential to provide a new target for drug discovery and development of immunotherapeutics.Read moreRead less
Modelling The Impact Of Global Climate Change On The Epidemiology Of Infectious Diseases In Bangladesh
Funder
National Health and Medical Research Council
Funding Amount
$118,988.00
Summary
Climate change may impact on human health via a change in the distribution and pathogenicity of infectious diseases, particularly in the South Asian region. This study will use high quality environmental and clinical data from an established time-series collated in Bangladesh, to better inform mathematical models which may predict future changes in infectious diseases epidemiology. Accurate and valid modelling can be valuable in guiding future public health policy for vulnerable populations.
An Investigation Of Vibrio Cholerae Sialidase As A Target For Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural inform ....The prevalence of the disease Cholera still causes significant human mortality, in particular in underdevloped countries. The process that enables the cholera toxin to cause signficant damage is now partly understood. This research project will provide a range of chemical entities (probes) that have the potential of intervening in this process . These probes will be the basis for a drug discovery programme that targets toxin binding. Through molecular modelling based on protein structural information, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will be then further optimised for eventual pre-clinical investigation. The technology to be used in this project is comparable to that we have used in the discovery of the recently approved influenza drug, Relenza .Read moreRead less
Pre-clinical Development Of A Chemically Synthetic Anti-toxic Vaccine Against Malaria
Funder
National Health and Medical Research Council
Funding Amount
$165,000.00
Summary
Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortal ....Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortality is the realistic aim of malaria vaccine strategies. Traditional approaches seek to provide this clinical protection indirectly, by killing the parasite or by reducing parasite multiplication. To this end, current anti-malarial vaccines candidates seek to confer on the host parasiticidal immune mechanisms, which have as their target antigenic proteins expressed on the surface of the different stages of the parasite. No malaria vaccine is yet on the market. There exist several potentially competitive leads in late-stage pre-clinical-early stage clinical development, particularly recombinant proteins. The US Navy MUSTDO-25 DNA vaccines are not living up to their promise. Most leading “vaccine candidates” are polymorphic alleles. There are significant prospects for vaccine-induced selection of breakthrough variants. Multiple alleles may also prove cost-prohibitive for vaccine development. The novelty and uniqueness of this approach have contributed to the acceptance of this study for publication by Nature. The aims of this proposal are four-fold: i) to further rationalize the target through chemical synthesis of intermediates and partial structures; (ii) to examine antigenicity and immunogenicity in large experimental mammals, and undertake epitope mapping of human anti-GPI IgG responses; (iii) to obtain preliminary safety data in these animals; and (iv) to undertake a vaccine trial in a simian malaria model. We envisage objectives (i)-(iii) will take 12 months. Objective (iv) will proceed in the six months thereafter.Read moreRead less
Factors Affecting The Toxicity Of The Dinoflagellate, Gambierdiscus Toxicus, And The Development Of Ciguatera Outbreaks
Funder
Fisheries Research and Development Corporation
Funding Amount
$22,600.00
Summary
Objectives: 1. Define factors influencing ciguatoxin production by cultures of Gambierdiscus toxicus. 2. Examine reef disturbance effects & significance of genetic heterogeneity in G. toxicus in toxin production. 3. Establish requirements for growth & bloom formation by G. toxicus & other dinoflagellates
Neural Mechanisms Mediating Hypersecretion And Motility Patterns Induced By Enterotoxins
Funder
National Health and Medical Research Council
Funding Amount
$415,250.00
Summary
This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are ....This project aims to identify the nerve cells that are responsible for the massive oversecretion of water and salt seen with cholera and other diseases producing diarrhoea. Many of these disease act through specific toxins and, although the biochemical targets of these toxins are reasonably well understood, the nerve cells on which they act have never been identified. Furthermore, the mechanisms that couple the oversecretion with a massive increase in the propulsive activity of the intestine are also unknown. We will investigate each of these questions using the small intestine of the guinea-pig, because the nerve circuit in this preparation is better understood than that of any other. Nerve cells that respond to three specific toxins, each known to activate the nervous system via different mechanisms, will be determined using intracellular recording methods, injection of marker dyes and methods that allow the identification of their neurochemistry. This will allow the functions of responsive nerve cells to be identified and their places in the circuits that control secretion and propulsion to be determined. This information will be correlated with studies in whole animals being undertaken in Sweden so that potential sites for intervention can be identified.Read moreRead less