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.
Functional Genomic Analysis Of The NKT Cell Control Locus Nkt1 And The Bana3/Babs2 Lupus Susceptibility Locus
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of ....The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of white blood cells, termed NKT cells, plays an important role in keeping the T and B cells in check, and we have found that these cells are deficient in an inbred mouse strain, NOD mice, which develop lupus after exposure to a particular type of bacteria, called mycobacteria. We have found that one of the major genes conferring susceptibility to lupus in these mice lies in the same genetic region as the major gene controlling NKT cell numbers, raising the possibility that the deficiency in NKT cells in this strain predisposes it to developing lupus. The experiments proposed for this project are divided into two groups. The first group test whether increasing NKT cell numbers by either injecting them, or else transferring genes that allow more to develop naturally, can affect the risk of developing lupus. The second group of experiments examine the potential roles of two specific genes which are in the genetic region of interest, and which we think might control both NKT cell numbers and lupus susceptibility. The approach to be used involves sophisticated techniques of genetic analysis, such as the use of mutant mice which carry genetic mutations near the relevant genes, and congenic mice, which are like NOD mice, but carry in addition to NOD genes, genetic regions from a non-autoimmune strain.Read moreRead less
Identification And Characterisation Of Nessy; A Novel Gene Important For T Cell Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
This project aims to identify, and understand the function of, a new gene involved in the immune system. The Nessy mouse strain was developed in Prof. Goodnow s Medical Genome Centre at the Australian National University. It has a mutation in an unknown gene which causes a defect in T lymphocytes- white blood cells which are important for fighting infection. This project has three major aims: 1) to identify the gene. 2) to understand the defects in T lymphocytes caused by the gene. 3) to identif ....This project aims to identify, and understand the function of, a new gene involved in the immune system. The Nessy mouse strain was developed in Prof. Goodnow s Medical Genome Centre at the Australian National University. It has a mutation in an unknown gene which causes a defect in T lymphocytes- white blood cells which are important for fighting infection. This project has three major aims: 1) to identify the gene. 2) to understand the defects in T lymphocytes caused by the gene. 3) to identify which other genes interact with the mutant gene. Thus will allow us to understand how the mutant gene causes the T lymphocyte defects. This project will improve our understanding of the development and functioning of T lymphocytes, which play a central role in the immune system. Since the genomes of mice and humans are very similar, it is likely that we will be able to identify a human counterpart to the Nessy gene.Read moreRead less
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
Localisation Of Genes For Multiple Sclerosis In The HLA Region
Funder
National Health and Medical Research Council
Funding Amount
$426,500.00
Summary
Multiple sclerosis (MS) is a disease that affects around 10,000 Australians. It is a disease of young adults with women being affected more often than men. While there are therapeutics available to treat it, these are very expensive ($10-12,000 per annum) and are effective in only a proportion of affected individuals. MS is governed by a complex interplay of environmental and genetic susceptibility factors, neither alone sufficient to cause disease, however, the study of these factors has been c ....Multiple sclerosis (MS) is a disease that affects around 10,000 Australians. It is a disease of young adults with women being affected more often than men. While there are therapeutics available to treat it, these are very expensive ($10-12,000 per annum) and are effective in only a proportion of affected individuals. MS is governed by a complex interplay of environmental and genetic susceptibility factors, neither alone sufficient to cause disease, however, the study of these factors has been confounded by the complex nature of the disease. We and other researchers have identified the human leukocyte antigen (HLA) complex on chromosome 6 as harbouring susceptibility genes for MS. Our recent work has localised these genes in two distinct regions of the HLA complex. In this project we plan to localise these genes more precisely to permit their identification. By identifying these genes we hope to develop an understanding of their function in a healthy person and in a person with MS. Understanding what goes wrong during disease is a critical first step along the track to the design of novel therapeutics. A successful therapeutic agent would be designed to interfere with disease processes and treat the disease more effectively.Read moreRead less
Human Genetic Susceptibility To Bacterial Invasion And The Interaction With Chronic Helminth Infections
Funder
National Health and Medical Research Council
Funding Amount
$377,040.00
Summary
A genetic study will be undertaken to identify genes that increase an individual’s risk of developing a bloodstream bacterial invasion following severe pneumonia, a leading cause of infant death world-wide. The risk of getting a bacterial infection is increased in individuals already infected with parasitic intestinal worms. This may also reduce drug and vaccine efficacy. Research will be undertaken to investigate these relationships for future drug and vaccination development.
THE CMRF-35 FAMILY OF MOLECULES: GENE STRUCTURE, EXPRESSION AND FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$367,669.00
Summary
White blood cells are the army which fights invasion by foreign organisms or cancer cells. Their main artillery and communication systems are located on the cell surface as protein molecules. These recognize foreign material and danger signals, and signal into the cell to direct interactions with other cells- soluble molecules in the immune system. We have discovered a new group of molecules called the CMRF-35 family which are found on the surface of different white blood cells. We have characte ....White blood cells are the army which fights invasion by foreign organisms or cancer cells. Their main artillery and communication systems are located on the cell surface as protein molecules. These recognize foreign material and danger signals, and signal into the cell to direct interactions with other cells- soluble molecules in the immune system. We have discovered a new group of molecules called the CMRF-35 family which are found on the surface of different white blood cells. We have characterized two members of the CMRF-35 family by studying the structure of their genes and the cells which express them. These studies will determine if the known CMRF-35 molecules are able to send signals from the cell surface into the cell to activate or inhibit a functional response by cells that express them. We hope to identify the triggers that initiate a signal from CMRF-35 molecules into the cell and whether there are molecules which bind CMRF-35 molecules and then get moved from the surface to inside the cell. Our data suggests that there are other unknown members of this family. We will determine how many members there are in this family by studying the DNA of genes that are related to the known CMRF-35 molecules. This will allow us to charactertize novel molecules that may be important for white cell function. Discovering new white cell surface molecules and determining their function increases our understanding of how the immune response works. If these CMRF-35 molecules represent a large family, it is highly likely that they have important roles in the immune response. By understanding the signals these molecules send to the cell nucleus we may be able to exploit their function to fight disease. For example where the immune system has not recognized cancer cells as dangerous, we might use the activating CMRF-35 molecules to stimulate a response. In the case of auto-immunity we may be able to reduce the responses via inhibitory CMRF-35 molecules.Read moreRead less
Characterisation Of Polymorphism In HIV-1 Sequence: Investigation Of Viral Escape From HLA-restricted Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in ....Although drug therapy has been developed for treatment of HIV infection, there are many aspects of optimal long-term therapy that are problematic. An important reason for this is that HIV disease is different in different individuals, and we believe this is in large part attributable to the way in which the virus can escape an individual's unique immune responses against it. HIV has been shown to escape by mutating and evolving during infection, but the nature and extent to which this occurs in everyone is not established. This is an important barrier to the design of effective vaccines against HIV. This study uses a novel method to describe the ways that HIV evolves uniquely in every individual, and to determine how this information relates to subsequent disease severity, response to therapy and response to vaccination. This will allow HIV infected patients to have better 'individualised' therapy as well as help in the design of effective vaccines.Read moreRead less
The Immunogenetics Of Ankylosing Spondylitis: A Genetic And Functional Investigation Of IL23R And Related Genes
Funder
National Health and Medical Research Council
Funding Amount
$536,679.00
Summary
Ankylosing spondylitis (AS) is a common inflammatory arthritis which causes primarily back pain and stiffness, and affects 1-250 individuals. Our group identified association between tagging genetic markers in the gene IL23R and AS, and our preliminary data suggests some related genes are involved as well. This study aims to identify the key genetic variants involved and determine the mechanism by which they cause AS.