Mechanisms Underlying Brain Metabolic Changes In Cerebral Malaria.
Funder
National Health and Medical Research Council
Funding Amount
$334,061.00
Summary
About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early symptoms are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection die and the remainder recover, sometimes with slight neurological impairment. During the cerebral malaria attack, the way that the brain ha ....About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early symptoms are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection die and the remainder recover, sometimes with slight neurological impairment. During the cerebral malaria attack, the way that the brain handles sugar, in order to make the energy needed for brain function, is changed. It adopts a pattern rather like a brain that has been starved of oxygen, though whether this actually occurs is not clear. An alternative idea is that this change in brain biochemistry is caused by cytokines. These are protein molecules produced by the immune system as part of the attack on the malaria parasite. Unfortunately, in excess it is known that some of them, particularly the one called tumour necrosis factor, can have deleterious effects on the host (in this case, human beings). Using an experimental model in mice, we will find out which of the two possibilities (lack of oxygen, over-stimulation by cytokines) is responsible for the biochemical changes in the brain in cerebral malaria. This is important because the brain is very susceptible to changes in the pathways that produce the energy needed for it to function properly. From this work we hope to find out better ways of treating cerebral malaria.Read moreRead less
The Effect Of Alteration Of Glucose Use On Brain Function
Funder
National Health and Medical Research Council
Funding Amount
$131,731.00
Summary
Glucose has long been accepted as the mandatory fuel for the brain although it is not fully understood why this is so. Impairment of the glucose supply to the brain results in impairment in brain functions, coma and ultimately death. As a result the body possesses rigid regulatory systems to maintain blood glucose levels within set limits. In certain conditions where blood glucose levels frequently drop below normal, the brain compensates by increasing the uptake of glucose into the brain thus k ....Glucose has long been accepted as the mandatory fuel for the brain although it is not fully understood why this is so. Impairment of the glucose supply to the brain results in impairment in brain functions, coma and ultimately death. As a result the body possesses rigid regulatory systems to maintain blood glucose levels within set limits. In certain conditions where blood glucose levels frequently drop below normal, the brain compensates by increasing the uptake of glucose into the brain thus keeping the glucose supply normal despite lower than normal blood glucose concentrations. In these conditions, which include diabetic hypoglycaemia unawareness, anorexia and starvation, the normal hormonal systems warning of low blood glucose are bypassed. However, despite normal glucose supply to the brain, the performance of the brain is still adversely affected. The electrical activity of the brain changes, reaction times slow, and vigilance is decreased. This implies that, despite the brain having a normal supply of glucose, the glucose is being used differently and that these differences affect the functional performance of the brain. The AIMS of this study are to determine: 1. How does the use of glucose vary in the hypoglycaemia unawareness state? 2. How do these variations effect the performance of the brain? The SIGNIFICANCE of this work lies in 1. Increasing our understanding of the role of glucose in the brain, 2. Increasing our understanding of how the brain works, and, 3. Increasing our understanding of why cognitive impairment occurs in disorders such as diabetes, anorexia and starvation and whether this impairment is reversible. 4. Developing application of a relatively new technique, functional magnetic resonance spectroscopy, for use study of biochemical and cognitive brain disorders.Read moreRead less
Structure And Interactions Of The Malarial Vaccine Candidate AMA1
Funder
National Health and Medical Research Council
Funding Amount
$351,000.00
Summary
Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial d ....Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial drugs. AMA1 is an asexual stage antigen and a leading vaccine candidate. Little is known about the function of this protein, but it has been proposed to play a role in invasion of red blood cells. A clearer understanding of the structure of parasite antigens such as AMA1 that induce a protective response in infected individuals would provide a stimulus to research into recombinant antigens as vaccines and a deeper understanding of host-parasite interactions. The aims of this project are to determine the three-dimensional structures of the three major structural domains of AMA1 and of the complete AMA1 antigen. We shall also determine the structures, both in aqueous solution and bound to AMA1, of small peptides identified by phage display as being capable of binding to AMA1 and blocking parasite entry into red blood cells. The overall goal of this work is to determine the structure of AMA1 and define the structural basis for its interaction with small peptides capable of blocking its activity as well as the structural features necessary for AMA1 to react with protective antibodies. The structure of AMA1 will provide a molecular basis for the design of engineered antigens capable of eliciting a protective immune response against AMA1. The inhibitory peptide structures will likewise provide a molecular basis for the design of non-peptidic blockers of AMA1. Either or both of these may be useful therapeutics leads in the fight against malaria.Read moreRead less
Structure And Interactions Of The Malarial Surface Antigen AMA1
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Malaria remains one of the most serious infectious diseases in the world today, being responsible for 1-2 million deaths annually. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial drugs. A clearer understanding of the structure of antigens in the parasite that induce a protective response in infected individuals would provide a stimulus to research into recombinant antigens ....Malaria remains one of the most serious infectious diseases in the world today, being responsible for 1-2 million deaths annually. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial drugs. A clearer understanding of the structure of antigens in the parasite that induce a protective response in infected individuals would provide a stimulus to research into recombinant antigens as vaccines and a deeper understanding of the host-parasite interaction. AMA1 is an asexual stage antigen and a leading vaccine candidate. Little is known about the function of this protein, but it has been proposed to play a role in invasion of red blood cells. The specific aims of this project are to determine the three-dimensional structures of the three major structural domains of AMA1 and of the complete AMA1 ectodomain. The interaction of one or more of these domains with Fab fragments of protective antibodies raised against intact AMA1 will then be investigated. We also intend to determine the conformations, both in aqueous solution and bound to AMA1, of oligopeptides identified by phage display as binding to AMA1 and blocking its binding to red blood cells. The overall goals of this work are to determine the structure of AMA1 and to define the structural basis for its interaction with antibodies and small peptides that are capable of blocking its activity. This information will provide a molecular basis for the design of either synthetic antigens capable of eliciting a protective immune response against AMA1 or peptidomimetic inhibitors of AMA1. Either or both of these may be useful in the prevention or treatment of malaria.Read moreRead less
Insulin-like Growth Factor (IGF)-II Binding Specificity Of IGF Binding Protein-6: Structural And Functional Studies.
Funder
National Health and Medical Research Council
Funding Amount
$265,630.00
Summary
Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like ....Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like a 'lock and key'. The aim of this project is to understand how IGFBP-6 binds to IGF-II by looking at its three-dimensional structure. Using this information, it may be possible to develop new treatments which can inhibit IGF-II activity and therefore may be useful in the treatment of some cancers.Read moreRead less