Genetic Control Of Susceptibility To Autoimmune Gastritis
Funder
National Health and Medical Research Council
Funding Amount
$346,945.00
Summary
Autoimmune gastritis is caused by the immune system targeting and destroying the stomach lining. We have developed a mouse model of the causes of gastritis and mapped the two major genes that can control susceptibility. This project involves the final stages of identifying these genes and determining how they cause disease.
Detection Of Susceptibility Genes For Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$589,073.00
Summary
Multiple sclerosis is one of the most common chronic diseases of the nervous system. It usually starts in young adulthood and continues with episodes of severe disability from which partial recovery leads in many patients to difficulties with walking, balance, speech, bladder control and other neurologic functions. The disease inflicts a severe burden on both patients and the community. There is currently no preventive treatment and therapy is expensive (interferon at $20,000 p.a.) and of limite ....Multiple sclerosis is one of the most common chronic diseases of the nervous system. It usually starts in young adulthood and continues with episodes of severe disability from which partial recovery leads in many patients to difficulties with walking, balance, speech, bladder control and other neurologic functions. The disease inflicts a severe burden on both patients and the community. There is currently no preventive treatment and therapy is expensive (interferon at $20,000 p.a.) and of limited benefit in stopping further damage and of no benefit in reversing existing damage. New treatments will come through a full understanding of how the immune system attacks the brain to cause MS. There is a strong inherited component in MS and the discovery of the genes responsible should speed up the quest to understand the cause of the disease. The proposed studies involve international collaboration co-ordinated from Cambridge University, UK, in which the entire human genome will be screened looking for the MS genes using world s best available technology. Funding of this grant will allow Australia an equal seat at the table for this collaboration involving 17 countries. No individual country can recruit enough patients and hence this international effort is essential. It is expected that the understanding of the cause of MS will lead to new treatments that are effective and with low side effects.Read moreRead less
Genomic And Functional Analyses Of A Novel Gene Implicated In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$732,439.00
Summary
We have recently discovered a novel gene that contributes to the development of juvenile diabetes. Unfortunately, very little is known about the function of this gene. To better understand how this gene affects the immune system and contributes to disease, we have generated a unique mouse strain that has a dysfunctional copy of this gene. These mice will enable us to characterise this gene and potentially establish a new area of research in diabetes prevention.
Identifying Genes In The HLA Complex That Influence Clinical Course And Susceptibility In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$725,177.00
Summary
There is no cure for multiple sclerosis (MS), but a person's genetic make-up can influence their susceptibility to developing MS and the symptoms of their condition. Knowing more about these MS genes will help to a) provide better advice concerning a person's risk of developing the disease or their prognosis b) in the design of new treatments. This project aims to identify 'MS genes in a region of the human genome call the HLA complex.
Genetic Analysis Of Migraine And Comorbid Psychiatric Disorders Using Twin Families
Funder
National Health and Medical Research Council
Funding Amount
$554,450.00
Summary
Typical migraine, is a frequent, debilitating and painful disorder that normally affects people during their most productive years (up to 25% of females and 7.5% of males in Western populations). Additionally, several studies have demonstrated a cross-sectional relation between psychiatric disorders (namely anxiety and depression) and migraine in community samples. The World Health Organization (WHO) recently identified migraine and major depression among the world's top 20 leading causes of dis ....Typical migraine, is a frequent, debilitating and painful disorder that normally affects people during their most productive years (up to 25% of females and 7.5% of males in Western populations). Additionally, several studies have demonstrated a cross-sectional relation between psychiatric disorders (namely anxiety and depression) and migraine in community samples. The World Health Organization (WHO) recently identified migraine and major depression among the world's top 20 leading causes of disability, with an impact that extends far past the suffering individual, to the family and community. In both sexes of all ages, depression and migraine are the 1st and 19th leading causes of disability affected life years. Although both migraine and depression are highly prevalent in our society, their aetiologies remain relatively obscure and there are no laboratory based diagnostic tests that identify those who suffer from the disorders. Because so little is known about them, a positional cloning approach is the only feasible way to identify the molecular mechanisms underlying these disorders. This project will collect a sample with sufficient power to perform a genome wide linkage screen to i) identify novel susceptibility genes, and ii) confirm previously reported susceptibility genes for migraine and co-occurring psychiatric disorders. The susceptibility genes identified (and confirmed) in this sample will provide clues to the further elucidation of the complex molecular pathways of migraine (and co-occurring psychiatric disorders) and, finally, will help in the development of diagnostic tests and rational treatment strategies.Read moreRead less
Identification And Characterisation Of The Genes And Pathways In Susceptibility To Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$575,581.00
Summary
One of the greatest challenges facing contemporary genetics is to understand the genetics of complex diseases such as inflammatory bowel disease, mutiple sclerosis and schizophrenia. This application seeks to unravel the complex interactions between susceptibility genes and environmental triggers that work together to produce the inflammatory bowel diseases (IBD). Current estimates of the prevalence and incidence suggests that there may be 30-40,000 Australians who suffer from these chronic debi ....One of the greatest challenges facing contemporary genetics is to understand the genetics of complex diseases such as inflammatory bowel disease, mutiple sclerosis and schizophrenia. This application seeks to unravel the complex interactions between susceptibility genes and environmental triggers that work together to produce the inflammatory bowel diseases (IBD). Current estimates of the prevalence and incidence suggests that there may be 30-40,000 Australians who suffer from these chronic debiltating set of diseases known separately as Crohn's disease and ulcerative colitis. One susceptibility gene for Crohn's disease has been recently been identified and the project outlined will extend our knowledge not only to the susceptibility genes themselves, but also to the genes that interact with them to produce the disease via a cascade of immune and inflammatory events. This work is part of a large international effort to identify all IBD susceptibility genes and builds on the resources of the Australian IBD Familiy Register- an Australia wide register of families in which multiple members are affected by CD or UC. A traditional gene mapping approach is used in concert with mutiple analyses of different gene expression profiles in disease versus normal bowel tissues as well as in cell lines from patients versus controls. Validation studies include identification of the particular tissues and cell types that are involved in the pathological immune response typical of IBD as well as characterisation of specific patient genotypes and- or phenotypes that may correlate with expression profiles. Results obtained will be used to identify genes underlying IBD susceptibility, the mutations that drive the disease and eventually therapeutic targets for modulation and treatment of disease.Read moreRead less
One of the interesting questions in human biology is why monozygotic twins, which have an identical genetic make up, can still vary in many complex traits such as height, eye colour and susceptibility to various mental and disease states. It is clear that this variation is not always due simply to environment. We propose in this application to show that, even if the genetic code is identical in monozygotic twins, epigenetic marks such as DNA methylation and histone modifications can vary between ....One of the interesting questions in human biology is why monozygotic twins, which have an identical genetic make up, can still vary in many complex traits such as height, eye colour and susceptibility to various mental and disease states. It is clear that this variation is not always due simply to environment. We propose in this application to show that, even if the genetic code is identical in monozygotic twins, epigenetic marks such as DNA methylation and histone modifications can vary between critical genes giving rise to differences in gene expression patterns. We propose that the variation in the methylation pattern arises after the two embryos have split, at a time when the developing embryo undergoes genome-wide demethylation followed by de novo re-methylation. The importance of this project is NOT what it tells us about twins themselves, but that twins can provide the clue to disease processes which affect everybody in the population. The results of these experiments will determine the extent to which epigenetic changes to the genome that occur early in embryonic development provide an additional source of variation in gene expression that could contribute to phenotypic variation. By using identical twins we eliminate the possibility that epigenetic modifications that we observe are themselves influenced by genotype. Determining these epigenetic differences will provide an insight into the mechanisms underlying complex traits and human disease.Read moreRead less
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
Regulating Tolerogenic Signals By Inhibitory Co-receptors
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke immunological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We w ....Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke immunological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We wish to determine if PECAM-1 functions as an inhibitory receptor in the lymphoid microenvironment using genetically engineered mice which lack the protein. As some of the functional features may display modest features, we plan to cross the PECAM-1 deficient mice with hen egg lysozyme transgenic mice to test the importance of PECAM-1 in peripheral tolerance. We will also define its importance in T cell function. We will test if the PECAM-1 deficient mice are more susceptible to the onset of inducible autoimmunde diseases including mouse models of collagen-induced arthritis and diabetes. Finally, we will produce transgenic mice expressing normal and disabled signaling motifs of PECAM-1 to test their requirement in autoimmunity.Read moreRead less