We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a ....We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a body of evidence that suggests the following interactions between inflammatory cytokines and salicylate, with important practical ramifications, in children. 1. Salicylate toxicity, like the acute multi-organ form of childhood malaria it mimics, is probably caused by excess systemic iNOS induction. This plausibly includes the metabolic acidosis, hypoglycaemia, seizures, coma and cerebral oedema seen in both conditions. Both are thus logically susceptible to treatment with specific iNOS inhibitors. 2. The same picture would arise in children when smaller doses of salicylate synergise with IFN-g, IL-1b, and perhaps other cytokines induced by malaria as well as by viruses. This gives the first proposed explanation for Reye's syndrome, defining the circumstances in which it occurs, and predicting a rationale for its treatment. Through the parallels seen in different age groups in malaria and aspirin toxicity, it also rationalises the difference in childhood vs adult malaria syndromes. 3. The overall severity and mortality of childhood malaria in East Africa may be worsened, through this cytokine-salicylate synergy, by home treatment with aspirin when children first become ill. 4. A relative absence of salicylate intake by children in various malarial Pacific Islands may contribute to falciparum malaria being a less severe disease there than in East Africa.Read moreRead less
Trafficking And Expression Of PfEMP1 On The Surface Of P.falciparum-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Malaria causes over 2 million deaths each year. The parasite infects human red blood cells and expresses a virulence protein on the erythrocyte surface allowing it to adhere to the microcapillaries preventing clearance through the spleen. We aim to understand how the parasite is able to express this virulence protein on the parasite-infected red blood cell surface. Identification of the proteins involved will provide potential drug targets to develop novel antimalarial compounds and strategies.
Assessment Of Transgenic Plants Expressing Malaria Antigens As A Means Of Inducing Protective Immunity
Funder
National Health and Medical Research Council
Funding Amount
$112,000.00
Summary
Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focusses on the development of such an alternative, a vaccine against malar ....Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focusses on the development of such an alternative, a vaccine against malaria using plants transgenic for genes encoding vaccine molecules. Growing these plants not only provides a potentially inexpensive vaccine production system but also offers a potential delivery system such that immunisation may be possible simply through consumption of an edible vaccine. This project intends to investigate the possibility of using transgenic plants expressing malaria antigens to induce protective immunity against malaria infection. The results of this project will provide vitally important information in malaria vaccine production and delivery.Read moreRead less
Retinal Microvascular Signs In Acute Stroke: Prognostic Significance And Relevance To Underlying Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$375,425.00
Summary
This project will describe abnormalities of the blood vessels of the retina in patients with stroke. Stroke is a common problem affecting some 48,000 Australians each year. Despite medical progress, stroke is commonly fatal (the third leading cause of death) and the leading cause of serious acquired disability in older people. This project will obtain detailed photographs of patients admitted to hospital with acute stroke. The acquired digital images will be analysed using new methods that asses ....This project will describe abnormalities of the blood vessels of the retina in patients with stroke. Stroke is a common problem affecting some 48,000 Australians each year. Despite medical progress, stroke is commonly fatal (the third leading cause of death) and the leading cause of serious acquired disability in older people. This project will obtain detailed photographs of patients admitted to hospital with acute stroke. The acquired digital images will be analysed using new methods that assess size of the small retinal arteries compared to veins (the arteriole-to-venule ratio) and will document other abnormalities, such as microaneurysms, haemorrhages, tortuosity and focal and generalised vessel narrowing and wall opacity. In normal populations these signs are associated with hypertension, inflammation and endothelial dysfunction and predict future stroke. These signs, and their significance have not been systematically studied in acute stroke. This may offer a window into the brain for important subgroups of stroke such as lacunar stroke. It is increasingly hard (and remains technically very difficult) to study the cause of lacunar stroke, affecting 10,000 Australians each year, as lacunar stroke has a lower fatality rate (and thus few opportunities for post mortem studies) but a high disability rate. Lacunar stroke is known to be due to small vessel disease but the exact nature of this disease is unknown. Echocardiography (to identify heart and major blood vessel abnormalities) and carotid duplex scanning (to identify critical stenosis of the major blood supply to the brain) are commonly normal in this type of stroke, and brain scanning with computerised tomography (CT) or magnetic resonance (MR) merely shows the outcome of the small vessel disease. The eye develops as part of the brain and thus retinal vascular abnormalities could add important knowledge to our understanding of stroke and add clinically useful data in the assessment of patients with stroke.Read moreRead less
Antibodies Against Erythrocyte Invasion Ligands Of Plasmodium Falciparum And Protection From Malaria
Funder
National Health and Medical Research Council
Funding Amount
$358,184.00
Summary
Malaria is a leading cause of childhood death globally. Malaria parasites infect red blood cells and multiply inside them, resulting in severe illness if untreated. Currently there is no vaccine available and effective treatments are limited. In studies of children in Africa and PNG, we aim to identify immune responses that block infection and growth of malaria in the blood. With this knowledge, vaccines can be designed that target malaria to prevent serious illness and death.
Regulation Of The Epithelial Sodium Channel By The Nedd4-like Protein KIAA0439
Funder
National Health and Medical Research Council
Funding Amount
$452,640.00
Summary
The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the distal nephron of the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that aris ....The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the distal nephron of the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. Furthermore, ENaC and the molecules involved in the channel regulatory cascade are potential candidate genes in defining the genetic causes of human hypertension and salt wasting disorders. Previous studies from our laboratories and by other groups have implicated Nedd4, a protein initially cloned by us, as a key player in regulating ENaC. Our recent data suggest that KIAA0439, a close relative of Nedd4, is also involved in ENaC control mechanisms. The work proposed in this application is an extension of our recent findings and will enable us to fully define how KIAA0439 regulates the activity of ENaC.Read moreRead less
Mechanisms Of Nedd4/Nedd4-2-mediated Regulation Of The Epithelial Sodium Channel
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease me ....The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. Furthermore, ENaC and the molecules involved in the channel regulatory cascade are potential candidate genes in defining the genetic causes of human hypertension and salt wasting disorders. Previous studies from our laboratories and by other groups have shown that Nedd4 and Nedd4-2 proteins are key players in regulating ENaC activity. Our recent NHMRC supported work has identified another important protein, Grk2, as a regulator of ENaC. The work proposed in this application is an extension of our recent findings and will enable us to fully define how Nedd4-Nedd4-2 and Grk2 regulate the activity of ENaC.Read moreRead less
Dissecting The Molecular Basis Of The Malaria Parasite-Erythrocyte Tight Junction Complex
Funder
National Health and Medical Research Council
Funding Amount
$547,356.00
Summary
The parasites that cause malaria disease must invade the human red blood cell to complete their lifecycle. Invasion requires the formation of a complex interface between parasite and red cell called the Tight Junction. However, this structure's molecular makeup is entirely unknown. Our research will use a combination of state-of-the-art microscopy and genetics to define, for the first time, the junction's organization, providing a critical platform for the development of a malaria vaccine.
ASSESSMENT OF ENDOPLASMIC RETICULUM STRESS AND MUTATIONS IN MUCIN OLIGOMERIZATION DOMAINS IN ULCERATIVE COLITIS
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Ulcerative colitis affects 0.2% of Australians causing chronic or recurrent health morbidity and affecting employment. In severe cases it is life threatening. Its pathogenesis remains poorly understood. We have exciting and novel preliminary data from humans and informed by our unique animal models that make us propose that the disease is caused by Endoplasmic Reticulum Stress due to misfolding of mucin. We have designed fully powered prospective clinical and lab studies to test this hypothesis.