A Structural Investigation Into The T-cell Response To Epstein Barr Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$549,000.00
Summary
X-ray crystallography is an essential tool for solving the three-dimensional structure of proteins. Proteins control the biological processes within the cell and it is the precise shape of proteins that determines how they function. Depending on the particular sequence of the amino acids, the so-called building unit of the proteins, the protein molecule bends and forms a distinct, complex shape. This specific three-dimensional shape allows the protein to undertake its specific function, such as ....X-ray crystallography is an essential tool for solving the three-dimensional structure of proteins. Proteins control the biological processes within the cell and it is the precise shape of proteins that determines how they function. Depending on the particular sequence of the amino acids, the so-called building unit of the proteins, the protein molecule bends and forms a distinct, complex shape. This specific three-dimensional shape allows the protein to undertake its specific function, such as binding to other proteins, acting as an enzyme or interacting with nucleic acids. To determine how a protein acts, it is vital to know the precise three-dimensional shape at the atomic level. This proposal is concerned with understanding the precise shape of proteins that control the immune response to Epstein Barr Virus. Epstein Barr Virus is an ubiquitous human pathogen that has being linked to a number of cancers. This work will further our understanding of the immune response to Epstein Barr Virus.Read moreRead less
Major Xenoantigens For Neovascularised Porcine Xenografts: The Role Of PERV And MHC In Rejection And Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. Thi ....Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. This information can then be used to specifically remove or disable only those CD4 T cells capable of recognising the pig tissue and hence facilitate xenograft survival or tolerance without immunosuppression. In this way, the remainder of the CD4 T cell population and immune system is preserved intact. Recent studies have demonstrated that a pig virus (PERV) can be transmitted from pig tissue xenografts to recipient tissues. Our studies have also suggested that the process of xenograft rejection and the immunological recognition of transplant recipient cells infected with the pig virus, are closely related. We plan to investigate this relationship and ascertain whether the immunological destruction of the pig tissue xenograft is largely due to an immune response generated against the pig virus(es) it carries. As an extension of this concept, we will investigate whether long-term xenograft survival (tolerance) is associated with lack of immune reactivity to the pig virus and hence a continual capacity for pig virus to be transmitted to host tissues. This outcome could result in the development of unwanted disease(s) in transplant patients. To prevent these problems, our studies will determine whether it will be essential for such pig virus to be eliminated from the donor pig tissue before transplantation, e.g. by the development of potent anti-viral agents and-or via the development of pig herds that have been genetically engineered to be pig virus (PERV)-deficient.Read moreRead less
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
The Function Of Histidine-rich Glycoprotein In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$455,670.00
Summary
This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been im ....This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been implicated in controlling important aspects of inflammatory and cancer disease progression. Namely, HRG appears to regulate the formation and clearance of substances known as immune complexes - the primary cause of tissue damage in this disease. Furthermore, HRG may also control the process of cell invasion which is crucial for the migration of white blood cells of the immune system (leukocytes) to sites of inflammation to combat infections, and is also an important mechanism by which malignant tumour cells escape from primary tumour sites and spread throughout the circulation to other sites in the body. It is this process that makes cancer such a deadly disease. This study aims to define how HRG contributes to these important processes. This information may allow the development of new therapeutic approaches for the treatment of inflammatory diseases and cancer.Read moreRead less
Developing And Applying Biologically Plausible Statistical Models For Normal And Non-normal Family Data
Funder
National Health and Medical Research Council
Funding Amount
$339,700.00
Summary
Although molecular and computing advances have enabled more detailed investigations of inherited diseases and the ability to fit realistic statistical models to these data, limitations still exist when analysing family data. Often only basic statistical analyses are performed, due to the lack of understanding of complexities within the data and-or inability of researchers to fit appropriate statistical models. These factors have hampered the search for genes and environmental factors influencing ....Although molecular and computing advances have enabled more detailed investigations of inherited diseases and the ability to fit realistic statistical models to these data, limitations still exist when analysing family data. Often only basic statistical analyses are performed, due to the lack of understanding of complexities within the data and-or inability of researchers to fit appropriate statistical models. These factors have hampered the search for genes and environmental factors influencing common diseases. This project aims to develop novel, biologically realistic statistical models for investigation of common, complex diseases, such as heart disease and cancer, in families. These models will incorporate both measured and unmeasured genetic and environmental factors, and will be applicable to both normally distributed and non-normally distributed traits. Model fitting will use computer-intensive simulation techniques. Application of the models to data from two large pre-existing studies of international renown, the Victorian Family Heart Study and the Australian Prostate Cancer Family Study, will enable a better understanding of the genetic and environmental factors influencing heart disease and cancer. The models will also be applicable to many other studies of diseases which use data from families, and allow more accurate and useful information to be obtained from data. Software will also be made freely available to other researchers. This will ultimately translate into better outcomes from familial genetic research, and eventually, better prevention, detection, and treatment of the diseases.Read moreRead less
Induction Of Natural T-Regulatory Cells By Thymic Dendritic Cell Populations
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
In this study, we will determine the roles of the antigen presenting cells, namely denderitic cells, in the induction of T-regulatory cell (T-reg) developemnt in the thymus. T-reg cells play important roles in controlling the development of autoimmunity. This study will help to understand the possible causes of autoimmune diseases and to develop new treatments for these diseases.