Targeting Fungal Phospholipid Metabolism For Antifungal Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$828,557.00
Summary
Invasive fungal infections are a serious and escalating health problem. They cause severe disease with a high death rate and are very costly to the health system. New antifungal drugs with novel properties are needed now because there are problems with current drugs. This project aims to develop potent new antifungal drugs that are effective in many fungal diseases and are well-tolerated.
Regulation Of Secretion Of The Fungal Virulence Determinant, Phospholipase B
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted ....Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted by the disease-causing fungus, Cryptococcus neoformans, and that it is important in enabling the fungus to invade the host's cells and spread around the body from the lungs to the brain, where it can cause meningoencephalitis. PLB is also produced by other disease-causing fungi. The mechanism of PLB secretion is completely unknown. In this project we aim to determine the pathways involved in PLB secretion with the intention of exploiting steps unique to pathogenic fungi, for the future design of new anti-fungal drugs.Read moreRead less
Invasive fungal infections are a serious, escalating health issue. They cause severe disease with high death rates and are very costly to the health system. Current drugs often have suboptimal efficacy and cause side effects. New drugs are needed urgently. Many fungi, including the AIDS-related pathogen, Cryptococcus neoformans, secrete phospholipase B (Plbp) to facilitate infection. We will identify and investigate the Plbp secretion pathway as a novel anti-fungal drug target.
Cryptococcal Meningoencephalitis - Fungal Determinants Of Invasion Of The CNS
Funder
National Health and Medical Research Council
Funding Amount
$587,634.00
Summary
Meningitis and brain infection (meningoencephalitis) due to the fungus Cryptococcus, affect over 1 million patients with AIDS annually, especially in developing countries; with more than 600,000 deaths. It is not known how Cryptococci cross from the blood stream into the brain; this must be elucidated in order to prevent and/or control this devastating infection. This project will determine how cryptococci influence host blood cells to act as “Trojan horses” and/or release products that initiate ....Meningitis and brain infection (meningoencephalitis) due to the fungus Cryptococcus, affect over 1 million patients with AIDS annually, especially in developing countries; with more than 600,000 deaths. It is not known how Cryptococci cross from the blood stream into the brain; this must be elucidated in order to prevent and/or control this devastating infection. This project will determine how cryptococci influence host blood cells to act as “Trojan horses” and/or release products that initiate invasion of brain tissue and meningitis.Read moreRead less
Signalling Pathways And Fungal Virulence – The Inositol Polyphosphate Kinase Pathway In Cryptococcus Neoformans
Funder
National Health and Medical Research Council
Funding Amount
$545,189.00
Summary
Bloodstream fungal infections kill millions of people per year world-wide and are costly to treat. A potentially fruitful strategy for developing new, urgently-needed drugs to fight these infections, is to target signalling pathways, which in fungi, are essential for establishing infection. This proposal investigates how one such pathway, the inositolpolyphosphate kinase pathway, allows fungi to establish infection and will determine which components are suitable targets for drug development.
The prevalence of asthma in Australia is amongst the highest in the world yet no trials of primary prevention have been conducted which address the most common known causative agent (housedust mite allergens) and the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of interventions which address these factors is certain, the value of the wide array of advice given to asthmatics by various health institutions will not be known. We are applying to continue ....The prevalence of asthma in Australia is amongst the highest in the world yet no trials of primary prevention have been conducted which address the most common known causative agent (housedust mite allergens) and the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of interventions which address these factors is certain, the value of the wide array of advice given to asthmatics by various health institutions will not be known. We are applying to continue the Childhood Asthma Prevention Study (CAPS) which has been underway since mid-1997. CAPS is a randomised controlled trial in which 616 infants at high risk of developing asthma because of a family history have been enrolled. The interventions include allergen reduction and dietary supplementation with omega-3 fatty acids. The interventions are designed to have maximum effect but be simple to implement by parents. Several measures of compliance are being collected and regular contact is maintained though telephone calls and frequent home visits. Objective and subjective measurements of exposures, atopy, diet and asthmatic symptoms are being collected at 3 month intervals and at medical assessments when the children are 18 months, 3 and 5 years old. It is essential that we continue the study until all children are aged 5 and we will be able to test conclusively whether the interventions have had a positive effect. If so, CAPS will form the basis for a nationwide public health campaign which will have the potential to reduce the incidence of childhood asthma in Australia.Read moreRead less
Exploration Of Exposures Associated With Bedding That Are Risks For Childhood Allergy And Asthma Symptoms
Funder
National Health and Medical Research Council
Funding Amount
$263,500.00
Summary
Asthma prevalence in Australia has doubled in the last 20 years, with 1 in 4 children now affected. House dust mites are probably the single most important allergen associated with asthma. The prevalence of mite allergy is linked to exposure, and such allergy when combined with high exposure, is a potent risk factor for asthma exacerbations. The current international advice for managing mite-allergic asthma, strongly advocates the use of bedding encasings as the best way to reduce exposure. Howe ....Asthma prevalence in Australia has doubled in the last 20 years, with 1 in 4 children now affected. House dust mites are probably the single most important allergen associated with asthma. The prevalence of mite allergy is linked to exposure, and such allergy when combined with high exposure, is a potent risk factor for asthma exacerbations. The current international advice for managing mite-allergic asthma, strongly advocates the use of bedding encasings as the best way to reduce exposure. However, three recent major trials using encasings and a meta-analysis of earlier trials all fail to show a clinical benefit. One of the applicants (ET) recently showed, using expertise in measuring personal exposure, that these encasings, as used, fail to significantly reduce aeroallergen exposure. By contrast, 3 recent Australian studies, involving the applicants, AK, ALP and NG showed that feather bedding compared to synthetic bedding, was strongly protective for asthma - the opposite of public advice. The suggested mechanisms involve reduced exposure to mite allergens, or altered exposure to bacterial endotoxin, but persuasive experimental support is lacking. We also propose a novel hypothesis that feather exposure may induce allergic 'tolerance'. Currently there is a lack of certainty about valid approaches to prevent asthma, and the Global Initiative for Asthma has described the need to understand mechanisms and improve interventions as urgent. This project is an ideal opportunity to combine the expertise of the CIA (ET) in measuring airborne exposures (mite, endotoxin, proteins) with that of the others who have expertise in children's asthma, and who are already involved in two large clinical trails involving different bedding and allergen avoidance. Our measurements of these bedding exposures and their clinical outcomes will provide, for the first time, a quantitative basis to refine public health allergen-based interventions to prevent and manage asthma.Read moreRead less