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
Mechanisms Controlling Antibody Production By Modulating B Cell Antigen Receptor Signalling
Funder
National Health and Medical Research Council
Funding Amount
$536,628.00
Summary
This project will analyse mechanisms that regulate antibody production in health and disease. In health, antibodies are normally made exclusively against infectious agents, providing long-lasting immunity. Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where antibodies are made against innocuous elements of our environment, or resul ....This project will analyse mechanisms that regulate antibody production in health and disease. In health, antibodies are normally made exclusively against infectious agents, providing long-lasting immunity. Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where antibodies are made against innocuous elements of our environment, or result in uncontrolled B cell accumulation in lymphoma, leukemia and myeloma. In order to develop rational, specific methods for treating these diseases, it is necessary to identify and understand the biochemical mechanisms that normally control antibody formation against infectious agents, self components, and innocuous environmental agents. The project focuses on defining the biochemical mechanisms by which the antibody-forming cells, B lymphocytes, sense infectious, innocuous, or self components. These cells carry specific receptors that bind these components and transmit signals into the B lymphocyte. The research will determine how different types of signal are transmitted by the receptor so that, normally, large amounts of antibody are made against infectious agents but very little antibody is made against self components, and that B cell accumulation is tightly limited. By identifying how the types of signals are changed, the results of this project will reveal control mechanisms that may be altered in autoimmunity, allergy, immune deficiency, or lymphoma, and that may be able to be used as drug targets to cure these diseases.Read moreRead less
Mechanisms Controlling Antibody Production By Modulating B Cell Antigen Receptor Signalling
Funder
National Health and Medical Research Council
Funding Amount
$452,125.00
Summary
This project will analyse mechanisms that regulate antibody production in health and disease. In health, antibodies are normally made exclusively against infectious agents, providing long-lasting immunity. Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where antibodies are made against innocuous elements of our environment. In order ....This project will analyse mechanisms that regulate antibody production in health and disease. In health, antibodies are normally made exclusively against infectious agents, providing long-lasting immunity. Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where antibodies are made against innocuous elements of our environment. In order to develop rational, specific methods for treating these diseases, it is necessary to identify and understand the biochemical mechanisms that normally control antibody formation against infectious agents, self components, and innocuous environmental agents. The project focuses on defining the biochemical mechanisms by which the antibody-forming cells, B lymphocytes, sense infectious, innocuous, or self components. These cells carry specific receptors that bind these components and transmit signals into the B lymphocyte. The research will determine how different types of signal are transmitted by the receptor so that, normally, large amounts of antibody are made against infectious agents but very little antibody is made against self components. By identifying how the types of signals are changed, the results of this project will reveal control mechanisms that may be altered in autoimmunity, allergy or immune deficiency, and that may be able to be used as drug targets to prevent unwanted antibody production to cure these diseases.Read moreRead less
Role Of Transition Metal Ions And Redox Activity In The Development Of Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability ....Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability to generate free radicals is controversial. This study will employ a novel, minimally-invasive, technique to assess the nature and quantity of metal ions present in well-defined human and animal lesions at different stages of lesion development. The ability of these metal ions to catalyse free radical formation from components present in the artery wall will also be assessed. The release of these metal ions from the artery wall to added organic molecules will be assessed as this might minimise their potential to cause damage, and provide a possible therapeutic strategy. These studies will therefore provide valuable information as to the significance and role of reactive metal ions in the development of human artery disease and the possible prevention, or minimisation, of such processes.Read moreRead less
Saccadic Eye Movements And The Neural Basis Of Visual Perception
Funder
National Health and Medical Research Council
Funding Amount
$570,828.00
Summary
The eye has a restricted central area that has good vision. We must make very frequent eye movements to build up a high resolution picture of a particular image. The term active vision is used to describe the requirement of coordinating the eye movements with the visual system. The study of active vision at the neural level requires experiments that combine single cell recording with behaviour. This study will explore which parts of the brain are involved in active vision in monkeys.
HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional thro ....HIV-1 infection is characterised by high levels of virus replication and a progressive loss of immune cells, particularly CD4+ T lymphocytes. Highly active antiretrovial therapy (HAART) for HIV-1 infection results in profound suppression of viral replication, a substantial increase in CD4+ T lymphocytes and a decrease in morbidity and mortality. The primary source of T lymphocytes in early human development is the thymus. Recently, it has been demonstrated that the thymus remains functional throughout adult life. The role of the thymus in HIV-1 infection remains controversial. Studies of the role of the thymus in HIV-1-infected individuals has been limited by the lack of a marker of thymic function in vivo. We have recently developed a novel assay to quantify cells of recent thymic origin by taking advantage of certain molecular events that occur in the thymus during the production of new T lymphocytes. This molecular event creates a circular piece of DNA, called a T-cell receptor excision circles (TREC). TREC concentration in the periphery will increase with an increase in thymic output but will reduce in the presence of T cell proliferation or cell death. In order to determine the contribution of the thymus to immune reconstitution following HAART, we plan to study the dynamics of thymus function in HIV-1 infection by measuring TREC and T cell turnover in HIV-1 infection prior to and following HAART. In a subgroup of individuals, more commonly seen following treatment of HIV-1 infection in children, there is an increase in CD4+ T lymphocytes in the absence of a significant reduction in viral suppression. The role of the thymus in this unique subset of individuals will be studied.Read moreRead less