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Placental Malaria, Placental Function, Nutrient Transport And Fetal Growth Restriction
Funder
National Health and Medical Research Council
Funding Amount
$483,517.00
Summary
Malaria infection in the placenta impairs the baby's growth, probably by causing placental inflammation. We believe this inflammation interferes with the ability of placental cells to transport nutrients such as amino acids and glucose from mother to baby. We will test this by examining the expression of genes and proteins involved in nutrient transport in placental samples from pregnant women, and in cell lines, and will examine how malaria affects growth factors that control this process.
Molecular Cascades Determining Asexual-sexual Development In Echinococcus Granulosus
Funder
National Health and Medical Research Council
Funding Amount
$312,576.00
Summary
Hydatid disease is a zoonosis caused by the dog tapeworm Echinococcus with millions of people-animals infected. After decades of study, effective treatment remains a major challenge. We will use a combination of recently developed techniques to isolate specific genes associated with Echinococcus differentiation. Understanding how these genes are controlled will increase our sparse knowledge of the developmental biology of this important parasite and provide new clues for more effective therapies
Regulation Of Actin Polymerization During Malaria Parasite Invasion Of The Human Erythrocyte
Funder
National Health and Medical Research Council
Funding Amount
$318,147.00
Summary
Malaria parasites depend on successful invasion of red blood cells for their survival. Invasion is powered by a molecular motor based on two key proteins: actin and myosin. Non-specific drugs that inhibit parasite actin block invasion, demonstrating how important its regulation is to parasite success. This project will study several newly identified malaria actin-regulators, aiming to identify new drug targets that will block malaria actin function, stop motility and as such prevent disease.
The Quinoline Antimalarials: Mechanisms Of Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite f ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite feeds on haemoglobin. We propose that the parasite develops resistance to chloroquine by excluding either the drug or the toxic by-products from the site of action. We further propose that proteins of the digestive vacuole of the parasite are involved in the development of resistance to chloroquine. We plan to identify and characterise these proteins and to use this information to design novel antimalarial drugs.Read moreRead less
Mechanisms Of In Vivo Modulation Of Granulomatous Inflammation In Human Schistosomiasis
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Schistosomiasis is a serious parasitic disease responsible for up to 300,000 deaths annually. The cause are blood flukes that produce considerable disease severity, resulting from host inflammation against the parasite eggs lodging in the liver, giving rise to fibrosis, liver damage, enlarged spleen and death. The pathogenesis is regulated by molecules called cytokines and this project will unravel the mechanisms that regulate disease progression to the severe forms of chronic schistosomiasis.
Use Of Peptides From Phage Display Libraries To Probe The Function Of AMA-1 And Other Malaria Surface Proteins
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is cu ....Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is currently one of the leading asexual stage vaccine candidates. While antibodies to AMA-1 prevents malaria invasion, little is known about the role of the antigen in the invasion process. The aim of this proposal is to investigate the molecular interactions that makes AMA-1 an important player in the invasion process. We propose to map the regions of AMA-1 responsible for binding a set of peptides which we have isolated from random peptide libraries. Since these peptides inhibit the invasion of parasites into red blood cells, regions of AMA1- that bind these peptides will be of functional significance. A further outcome will be the identification of peptide residues essential for the inhibition of invasion followed by in vitro evolution of these peptides to improve their binding and inhibitory properties. A molecular description of how AMA1 binding peptides prevent parasite invasion of host erythrocytes will improve our understanding of the invasion process, and aid in improving vaccines based on AMA-1. Furthermore, this peptide-AMA-1 interaction will be assessed as a possible target for the development of novel anti-malarial therapies. Using random peptide libraries we have selected peptides that specifically bind to other merozoite surface proteins thought to be involved in merozoite invasion of erythrocytes. The ability of these peptides to inhibit merozoite invasion will be examined and characterised as described above.Read moreRead less
Characterization Of The Chloroquine Resistance Transporter Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$400,527.00
Summary
The malaria parasite is a single-celled organism which invades the red blood cells of its host. The aim of this project is to characterise the mechanism by which parasites have become resistant to the antimalarial drug chloroquine. Resistance is conferred by small changes in a single protein, but the underlying mechanism is not known. The results of this project will constitute a major advance in our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.
Coenzyme A Synthesis In The Human Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. This work focuses on a particular biochemical pathway in the human malaria parasite, Plasmodium falcip ....Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. This work focuses on a particular biochemical pathway in the human malaria parasite, Plasmodium falciparum. The pathway mediates the conversion of the nutrient, vitamin B5, into a molecule called Coenzyme A. It plays an essential role in the intraerythrocytic parasite and our preliminary data indicate that components of this pathway hold significant potential as antimalarial drug targets. In this project we will use a range of biochemical and molecular biology approaches to characterise in detail the components of this pathway in the parasite and to explore the possibility that compounds that inhibit this pathway may be of value as much-needed new antimalarial agents.Read moreRead less
Plasmodium Falciparum Neutral Aminopeptidases: Structure-function Analysis For The Discovery Of Anti-malarial Drugs.
Funder
National Health and Medical Research Council
Funding Amount
$634,027.00
Summary
Malaria is the world's most prevalent parasitic disease. Due to the spread of drug resistant parasites there is an urgent need to identify new anti-malaria targets and develop new drugs. We have shown that two enzymes, termed neutral aminopeptidases, are essential to the parasite's survival in the host. In this proposal we will obtain the structure of these enzymes and bring forth novel lead compounds that will form the basis of a new class of anti-malaria treatment.