Role Of NK Receptors In Susceptibility And Resistance To Human Malaria
Funder
National Health and Medical Research Council
Funding Amount
$546,588.00
Summary
Malaria kills 2 million children every year. However, many eventually become resistant to the disease. What causes some kids to die, and how others become resistant, is unknown. We believe that genes for Natural Killer molecules in the immune system can protect people against malaria, but can also over-react in the wrong way and make things worse. We plan to investigate the role of Natural Killer genes in causing disease and also protecting in young children in Papua New Guinea against malaria.
In Vivo And In Vitro Studies Of The Human -308 TNF Promoter Polymorphism.
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarif ....The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarify some of these questions, we will generate genetically modified mice that have either of the two genetic forms of the human TNF promoter. These mice will be compared in two models of associated disease, murine Lupus and cerebral malaria. We will also characterise the interactions of TPF1 with other components of the TNF control region. An understanding of the role of TPF1 in controlling TNF expression and an appreciation of the cell types that are able to express the phenotype, will allow the development of more subtle, cell specific strategies to modulate the activity of TNF without completely abolishing expression and may lead to better preventative and therapeutic strategies.Read moreRead less
Genetic And Phyisological Regulation Of KIR2DL4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A si ....Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A single copy of the mutant gene protects against malaria (advantageous) but a double dose of the gene results in sickle cell anaemia, which is fatal. Both the mutant and original gene are maintained in the population as the number of people dying from sickle cell anaemia is less than the number who would die from malaria if the mutant gene did not exist. This phenomenon is known as balancing selection. There are many examples of balancing selection and for each example there is usually a medical condition associated with a double dose of the mutant gene. We have discovered a new example of balancing selection in one of the genes used by the immune system. Very little is known about the function of this gene. In fact the literature abounds with contradictory findings concerning this gene. Our discovery that a mutant gene is present at very high frequency in the population helps explain these contradictory findings and places us in a very strong position to achieve a much better understanding of the function of this gene. We propose to investigate the basic biology of this gene and how it used in the immune system in order to obtain clues as to which medical condition this mutation may be relevant to.Read moreRead less
Identification Of Antigen Selection In The Human IgE Response By Analysis Of Somatic Point Mutations
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are ....Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are too low to allow their direct study. We have recently applied molecular biological techniques to study the genes that encode IgE antibodies. Our work suggests that the IgE response can sometimes develop in a different way to that of other antibodies (eg IgG). On the other hand, laboratory (in vitro) studies over many years support the possibility that IgE and IgG develop in parallel. In this study, we wish to identify circumstances in which IgG-like IgE antibodies develop. We therefore wish to study patients with different kinds of allergic disease, and patients with other conditions that are associated with IgE production. We therefore wish to study patients who have infections with parasitic worms. We deduce the processes that give rise to IgE antibodies by analysing patterns of mutations that accumulate in antibody genes during an immune response. Over recent years, we have developed new approaches to the analysis of such mutations, and this project also seeks to further develop our mutation analysis. This more powerful analysis will be applied to the study of mutations in the IgE genes seen in different patient groups, and should allow us to quantify the proportion of IgE antibodies that develop in each way. A better understanding of the relative contributions of the two pathways to IgE, in different conditions, will transform our understanding of the IgE response, and open up new avenues for the investigation of the causes and treatment of allergic disease.Read moreRead less
Major Histocompatibility Complex (MHC) Genetics Of Ankylosing Spondylitis
Funder
National Health and Medical Research Council
Funding Amount
$568,612.00
Summary
Ankylosing spondylitis (AS) is the prototypic condition of a group of types of inflammatory arthritis called 'seronegative spondyloarthropathies'. These conditions are the most common form of inflammatory arthritis in white populations and occur worldwide. One third of the risk of developing AS is determined by genes within a region called the 'major histocompatibility complex' (MHC), in addition to the gene HLA-B27, the main gene causing AS. We aim to identify the remaining MHC genes.