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The Clag Gene Family Of P. Falciparum; Examining Roles In Cytoadherence, Rheological Properties Or Tissue Trophism.
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
There are approximately 500 million of cases of malaria per year worldwide and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by the sticking of red blood cells which contain malaria parasites to the lining of microscopic veins and blocking them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by the ....There are approximately 500 million of cases of malaria per year worldwide and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by the sticking of red blood cells which contain malaria parasites to the lining of microscopic veins and blocking them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by the acronym clag, for cytoadherence-linked asexual gene. Most Australians know of clag as a glue, and our data provides evidence that it sticks the parasitised red cells to veins via a protein called CD36 on the internal surface of veins. Our evidence for this has been published in two prestigious international journals. We propose here to examine the same gene in a mouse malaria model as it should be highly informative to see what effect destoying clag has on the disease in a living animal. Obviously this cannot be tested in people. It has now become clear that there are a number of slightly different clag genes and we do not know what the others do. We propose here that they may enable the parasitised red cells to stick to targets other than CD36 on the surfaces of veins, or affect blood flow of infected cells, or direct the parasitised red cells to other organs. The experiments that we propose should reveal whether these ideas are true.Read moreRead less
Application Of Protein Microarrays To Develop A Cross-Species Malaria Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$451,821.00
Summary
Malaria remains a significant public health problem worldwide. Five species of malaria parasites infect humans. The ideal vaccine would be effective against all five species. Using a novel protein microarray approach, we will identify Plasmodium proteins that may be excellent targets of a cross-species malaria vaccine. This research will build on Australia's current strengths in biotechnology and will result in significant economic benefits by facilitating the development of a malaria vaccine.
RECOMBINANT MALARIAL PYRIMIDINE ENZYMES AS DRUG TARGETS
Funder
National Health and Medical Research Council
Funding Amount
$229,750.00
Summary
Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug dev ....Malarial parasites have now developed resistance to most of the available drugs and there is an urgent need for drugs with new mechanisms of action. Institutions collaborating on the Malarial Genome Project have sequenced the majority of DNA in the 14 chromosomes. The nucleotide sequence available on the internet contains thousands of open reading frames (ORFs) which encode proteins essential for survival of the parasite. Many of these proteins are enzymes which are suitable targets for drug development. A knowledge of the molecular architecture of the active site of such enzymes provides a template for drug design. The malarial parasite, Plasmodium falciparum, can only synthesise pyrimidine nucleotides for DNA via the de novo pyrimidine pathway. We have cloned the genes encoding three of the enzymes of the de novo pathway using sequence information from the Malarial Genome Project. Dihydroorotase, orotate phosphoribosyltransferase, and OMP decarboxylase, catalyse reactions 3, 5 and 6 of the pathway. We have expressed these enzymes in the bacterium Escherichia coli enabling large-scale production of these drug targets. We propose to characterise the catalytic and inhibitory properties of these enzymes, and grow protein crystals for determination of atomic structures by x-ray diffraction. The structures will provide templates for rational design of new antimalarial drugs. In a second approach for develoment of new drugs, the 3 malarial enzymes will be screened against chemical libraries for inhibition of catalytic activity. The initial screen will utilise a high throughput Biacore 3000 instrument which detects strong interactions between a target enzyme and candidate inhibitors. A thorough knowledge of the catalytic mechanisms, the three-dimensional structures and novel first generation inhibitors of these 3 malarial target enzymes, will provide a strong basis for development of new antimalarial drugs.Read moreRead less
Disease Burden, Risk Factors And Treatment Of Knowlesi Malaria
Funder
National Health and Medical Research Council
Funding Amount
$95,564.00
Summary
Plasmodium knowlesi is a form of monkey malaria recently found to also cause increasing numbers of natural infections in humans in South-East Asia. This research will describe the burden of P. knowlesi malaria in an area of Malaysian Borneo. The risk factors for acquiring P. knowlesi malaria will be assessed. Finally the optimal treatment for non-severe cases of P. knowlesi and P. vivax malaria will also be evaluated by comparing the 2 currently recommended anti-malarial medications in Malaysia.
Functional Resolution Of PTEX, The Exporter Of Virulence Factors In Malaria Parasites.
Funder
National Health and Medical Research Council
Funding Amount
$625,212.00
Summary
Almost half a million people die each year of malaria and nearly half the world’s population are at risk. To eliminate malaria this century we will need new drugs and vaccine to fight the disease. One potential drug target are the molecular gateways called PTEX, that are used by parasites to export virulence proteins into their human host cells. This grant aims to understand how the PTEX molecular machines work so we can develop new drugs to block them and kill the parasites.
The transmission of malaria is dependent on gametocytes, the sexual stages of parasite development that are taken up by mosquitoes when feeding on an infected person. While gametocytes are not responsible for disease symptoms, it is clear that malaria eradication is not be possible without an understanding of their biology and the tools to prevent transmission. My research focuses on understanding the biology of gametocytes and identifying new drug targets for transmission blocking strategies.
Griseofulvin, A Novel Host-directed Antimalarial Drug
Funder
National Health and Medical Research Council
Funding Amount
$461,551.00
Summary
This grant is for a Phase II clinical trial to test an FDA & TGA approved drug for a new use as an antimalarial drug. The parasite uses an enzyme from the human RBC to help it replicate & early trials show this drug appears to disrupt the life cycle of the parasite. This Phase II clinical trial will test the drug on human subjects, & if successful, the drug will be a new and novel way in which to treat and prevent malarial infections in humans.
Malaria infects millions of people worldwide causing serious morbidity and mortality. However, individuals do not develop natural immunity to malaria even after years of exposure to the parasite. There have be a multitude of attempts to make a vaccine , with products going to clinical trials, but no vaccine is able to provide adequate protection for the long term. We recently showed that Plasmodium had evolved a mechanism to kill cells that protect in the long-term. This study will investigate t ....Malaria infects millions of people worldwide causing serious morbidity and mortality. However, individuals do not develop natural immunity to malaria even after years of exposure to the parasite. There have be a multitude of attempts to make a vaccine , with products going to clinical trials, but no vaccine is able to provide adequate protection for the long term. We recently showed that Plasmodium had evolved a mechanism to kill cells that protect in the long-term. This study will investigate the mechanism by which the parasite kill these cells, so that novel therapies can be designed.Read moreRead less
Development Of Novel Anti-malaria Drugs That Block Parasite Invasion
Funder
National Health and Medical Research Council
Funding Amount
$1,035,623.00
Summary
Malaria is a devastating parasitic disease that kills over 400,000 people a year. Antimalarial drugs play a crucial role in helping eradicate malaria but of great concern is that parasites are becoming resistant to current drugs. We are developing drugs that prevent parasites from invading and proliferating in human blood which causes malaria. We are also discovering how the drugs work with the aim of greatly improving their performance towards clinical uptake.
Malaria In Pregnancy: Exposure, Immunity And Complications
Funder
National Health and Medical Research Council
Funding Amount
$549,723.00
Summary
Increasing malaria control efforts may lead to lack of exposure needed to develop immunity. We will use plasma samples from Africa, PNG and Asia, and measures of immunity we have developed, to discover (1) which are the most important protective immune responses and (2) how are these affected by changing exposure or new drugs. Overall, we hope to identify markers of protective immunity that can be used to identify women at most risk of malaria in pregnancy and its complications