Structural Determinants Of Siah Ubiquitin Ligase Complexes
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that ....Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that proteins can be modified by the addition of a signaling protein called ubiquitin, and it is this modified form that is recognised for degradation. The degradation of these proteins occurs within a large protein complex called the proteasome, which recognizes the ubiquitinated protein substrates. The ubiquitination of proteins is a multistep process, the final step of which is catalyzed by a ubiquitin ligase, or E3 enzyme. It is the E3 which is able to recognize the protein to be degraded, and catalyze the transfer of ubiquitin onto that protein. The E3 proteins (or sometimes complexes) are a diverse group which have to recognize many different proteins, in order that they be degraded at appropriate times. We have been working on the protein Siah (seven in absentia homologue), a member of an E3 complex and important in controlled cell death, cell division and inflammatory responses. One part of the Siah protein is involved in binding proteins and targeting them for ubiquitination, though it is not known how Siah recognizes its targets. Using protein crystallography we have solved the 3D structure of this part of Siah and now propose to co-crystallize Siah with target proteins and binding partners so as to understand how Siah recognizes these proteins. Understanding the basis of these interactions will allow us to determine other potential targets for the Siah protein and also how we may be able to interfere with these interactions with therapeutic drugs.Read moreRead less
Modulation Of Leishmaniasis By The Proinflammatory Cytokines TNF
Funder
National Health and Medical Research Council
Funding Amount
$288,911.00
Summary
We have established a mouse model that has been genetically modified and cannot produce the cytokine tumour necrosis factor. This cytokine is secreted in the beginning of the inflammatory response. If these mice are infected with a parasite they are not able to heal the infection and die quickly. We can demonstrate that these mice cannot regulate the beginning inflammatory response and do not form a cellular infiltrate at the site of infection.
Mechanisms Of Dendritic Cell-induced T-cell Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$314,773.00
Summary
Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. Thes ....Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. These cells (dendritic cells) are genetically modified to express the molecular targets of the autoimmune response. This in turn switches off the response to these targets. In this project we will explore how these cells can be used to turn off cells of the immune system and if cells of the immune system in turn control the dendritic cell's ability to do this.Read moreRead less
The Role Of 14-3-3 Proteins In Regulating The Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
The immune response is the body's defense system. It's malfunction leads to many diseases such as immune deficiency, asthma and cancer. Thus, it is important to find genes controlling immunity. Significantly, mammals have amazing similarities with flies, in terms of genes controlling immunity. We have found a new regulator of fly immunity and will define how this gene functions in the immune system. This project will identify potential points of intervention for treating immune system disorders.
Autoimmune diseases are those caused by the body's immune system attacking the body's own tissues. One group of autoimmune diseases, termed the thyrogastric cluster appear to share genetic risk factors, because they tend to occur together - either in the same patient, or else in families. Some of the diseases within the thyrogastric cluster are known to be very complex genetically, while others appear to be much less complex. Furthermore, some animal models of autoimmune diease are genetically s ....Autoimmune diseases are those caused by the body's immune system attacking the body's own tissues. One group of autoimmune diseases, termed the thyrogastric cluster appear to share genetic risk factors, because they tend to occur together - either in the same patient, or else in families. Some of the diseases within the thyrogastric cluster are known to be very complex genetically, while others appear to be much less complex. Furthermore, some animal models of autoimmune diease are genetically simpler still. We have chosen to study the genetics of gastritis in mice that have had their thymuses removed on the third day of life, because this model has relatively few genes involved; we have found that only 4 genes affect the risk of disease. This means that it will give us the optimum chance of identfiying at least one of these genes. The methods used involve both selective breeding techniques and generating special gene transfer mice in which individuals from one strain will carry the inserted genes from another. In this way, we can identify exactly which genes affect the risk of disease. Once identified, the gene sequences will help us determine if the same gene plays a role in human disease, and if so, to develop new diagnostic tests and therapies.Read moreRead less
A Functional Genomic Approach To The Genetics Of Autoimmune (type A) Gastritis
Funder
National Health and Medical Research Council
Funding Amount
$467,640.00
Summary
The thymus produces white blood cells which defend the body from infections and cancer. Unfortunately, these white blood cells can also cause disease if they target the body's own tissues. These disesaes are called autoimmune diseases, and an example of such a disease is autoimmune (type A) gastritis, in which the white cells target the acid-producing cells of the stomach. The resulting damage can lead to the development of pernicious anaemia (vitamin B12 deficiency) and cancer of the stomach. T ....The thymus produces white blood cells which defend the body from infections and cancer. Unfortunately, these white blood cells can also cause disease if they target the body's own tissues. These disesaes are called autoimmune diseases, and an example of such a disease is autoimmune (type A) gastritis, in which the white cells target the acid-producing cells of the stomach. The resulting damage can lead to the development of pernicious anaemia (vitamin B12 deficiency) and cancer of the stomach. This project studies a mouse model of autoimmune gastritis with the aim of identifying the genes that encode susceptibility to the disease in this model. Ultimately, this information should help us to devise therapies that can be applied to the clinical situation. We have previously identified the locations of the genes which are responsible for causing gastritis in these mice. Two of them are very close together on one chromosome and appear to be very important because they have the strongest effects. Furthermore, there is some evidence that these genes may also be involved in determining susceptibility to diabetes and lupus. This project aims to further characterise these genes by locating them more exactly and by examining their effect on mice not normally prone to gastritis.Read moreRead less
The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a series of cell types that must decide upon an appropriate course. In general, this response is successful and protective. However, occasionally the cells make an inappropriate decision leading to problems. For example, allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as diabetes and multiple sclerosis result from inappropriate attack ....The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a series of cell types that must decide upon an appropriate course. In general, this response is successful and protective. However, occasionally the cells make an inappropriate decision leading to problems. For example, allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as diabetes and multiple sclerosis result from inappropriate attack upon our own tissues. Despite the clear importance of immune regulation for health, the number of different cell types involved and the complexity of their behaviour has made it difficult to predict and control the response. In this research program a new theory of immune regulation enables the reduction of the complex system to separate components that can be modelled by computer to predict the outcome. An improved predictive framework promises to have a major effect on our understanding and ability to control immune related diseases.Read moreRead less
It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of ....It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of depression. If true, this could have important practical implications for preventative mental health, in identifying those at greatest risk if depression and counselling them to avoid stressful situations. However, success in replicating this finding has been mixed, and this is possibly because another important risk factor, social support, has not been taken into account. We have DNA samples from over 5000 twins who have been assessed for depression and risk factors including SLE and SS. This will give us unprecedented power to estimate the importance of the genotype x environment interaction. We shall also type other genes that have been implicated in depression and check for interactions with life events and social support. Our results will inform preventative strategies in mental health practice.Read moreRead less