Molecular Interactions Of The Tetraspanins CD37, TSSC6 And CD151 In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$566,575.00
Summary
The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which ....The tetraspanins are a new type of protein that are found at the surface of cells. Cells of the immune system, such as white blood cells, display at their surface, up to 20 different tetraspanin proteins. However, the precise contributions of these tetraspanin proteins to immunity is still not clear, nor is it clear exactly how tetraspanin proteins differ from one another and why white blood cells need to display so many different tetraspanins. Using genetic technology we have created mice which are unable to express certain individual tetraspanin proteins at their cell surface. Excitingly, the immune systems of these mice are not normal, in particular one type of white blood cell, the T cell responds in an exaggerated manner to stimulation. These results suggest a role for tetraspanins in the control and regulation of the immune system. This project will extend these results and work out the precise molecular mechanism by which the tetraspanins exert this control. In the future, a full understanding of how tetraspanins control T cells may ultimately lead to novel ways of controlling the immune system.Read moreRead less
PrtFII, A Streptococcus Pyogenes Fibronectin Binding Protein, And Invasive Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$296,540.00
Summary
Our recent work revealed that, in the Aboriginal population, young age is a risk factor for severe invasive diseases caused by group A streptococcus. For group A streptococcus infection to occur, bacterial attachment is the first step. The bacterium attaches to host cells through interactions involving host fibronectin and the pathogen's fibronectin-binding proteins. We have found that streptococcal strains from severe disease cases are more likely to have the gene for PrtFII, a fibronectin bind ....Our recent work revealed that, in the Aboriginal population, young age is a risk factor for severe invasive diseases caused by group A streptococcus. For group A streptococcus infection to occur, bacterial attachment is the first step. The bacterium attaches to host cells through interactions involving host fibronectin and the pathogen's fibronectin-binding proteins. We have found that streptococcal strains from severe disease cases are more likely to have the gene for PrtFII, a fibronectin binding protein, than those from uncomplicated skin sores. In this application we propose to extend this observation and compare biochemical properties of PrtFII from strains belonging to the above two sets of collections. We hypothesise that PrtFII from invasive strains bind to fibronectin more tightly than the proteins from strains that cause uncomplicated infection. We also will test whether sera from invasive disease cases have lower titre of antibodies to the conserved region of PrtFII than sera from uncomplicated cases. A streptococcal vaccine by necessity has to be a multi-component vaccine to cover a wide spectrum of diseases and epidemiological differences. The study proposed here may provide a basis to argue whether or not to include PrtFII in such a multi-component vaccine.Read moreRead less
Dendritic cells are a very rare type of white blood cell which play a critical role in the initiation of the immune response. They are of particular interest to scientists interested in vaccination, as for a vaccine to work effectively, the vaccine must be presented to the rest of the immune system by the dendritic cell. It has only recently become apparent that there are several types of dendritic cell, and these different types of dendritic cell vary in their ability to present a vaccine to th ....Dendritic cells are a very rare type of white blood cell which play a critical role in the initiation of the immune response. They are of particular interest to scientists interested in vaccination, as for a vaccine to work effectively, the vaccine must be presented to the rest of the immune system by the dendritic cell. It has only recently become apparent that there are several types of dendritic cell, and these different types of dendritic cell vary in their ability to present a vaccine to the immune system. We have already identified some proteins that are expressed on the surface of only one type of dendritic cell. We will explore the possible use of these proteins as a means of delivering a vaccine to only one type of dendritic cell. This project will also identify new genes that are expressed in some types of dendritic cells but not others. These new genes whose expression does differ amongst the dendritic cells are potential targets for manipulating the immune system and ensuring more efficient vaccination.Read moreRead less
Polarized Trafficking Of E-cadherin In Epithelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$515,564.00
Summary
The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to ....The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. This trafficking has dual roles, firstly in delivering newly-made E-cadherin to the surface where it functions and secondly, in regulating its adhesive function. Our research in this project is focussed on the molecules and intracellular compartments that control the delivery of E-cadherin to the cell surface. E-cadherin must be sorted in order to be delivered to the correct side of the cell. Having previously discovered the sorting signal in E-cadherin, we will now identify the cognate adaptor protein(s) that accomplish this sorting. New imaging techniques allow us to study protein trafficking inside live cells. Such studies have recently revealed that E-cadherin passes through a recycling endosome compartment on its way to the cell surface. This unexpected route, and the structure and role of the recycling endosome will now be studied in detail in live cells. Finally we will compare the sorting and trafficking of E-cadherin with the closely-related N-cadherin protein, to determine whether there are inherent differences in their trafficking that could explain their opposite roles in tumour cells, where N-cadherin is substituted for E-cadherin and allows metastatic behaviour. These studies will provide important information for understanding the adhesive and tumour suppressive roles of E-cadherin. In addition our findings will generate information fundamental to our understanding of cell polarity and protein sorting.Read moreRead less
Angiopoietin-2, Aortic Inflammation And Cardiovascular Events
Funder
National Health and Medical Research Council
Funding Amount
$332,161.00
Summary
Based on detailed preliminary data, we plan to investigate the importance of a novel protein (the cytokine angiopoietin-2) in cardiovascular disease. The results of this study will clarify the role of this cytokine in vascular pathology and may provide an important target for novel therapy and-or diagnostic markers for cardiovascular disease progression.
The Role Of The Interaction Of The CMV M11 Immune Evasion Molecule With CD44 In Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Herpesviruses can cause infections that persist for the lifetime of the host. They have evolved many mechanisms to elude the host's immune response that would otherwise eliminate them. One memberof the herpesvirus family that is particularly adept at avoiding host immunity is cytomegalovirus. This virus, while not causing symptoms in healthy individuals, is a significant cause of disease and mortality in individuals with suppressed immune systems such as transplant and AIDS patients, and in the ....Herpesviruses can cause infections that persist for the lifetime of the host. They have evolved many mechanisms to elude the host's immune response that would otherwise eliminate them. One memberof the herpesvirus family that is particularly adept at avoiding host immunity is cytomegalovirus. This virus, while not causing symptoms in healthy individuals, is a significant cause of disease and mortality in individuals with suppressed immune systems such as transplant and AIDS patients, and in the fetus which has a poorly developed immune system. In the current project we will explore at a molecular level how a virus-encoded molecule called m11 interferes with the functions of a cellular receptor called CD44 that has a range of cell functions including cell migration, activation and proliferation and signal transduction. The interaction of m11 with CD44 modifies cell migration and is likely to affect cell activation. Defining how m11 mediates its affects will allow us to define strategies to develop potential antiviral therapies. As CD44 is also involed in contributing to a range of diseases where inappropriate inflammation develops it may be that m11, or derivatives of it, could be harnessed to ameliorate these inflammatory diseases.Read moreRead less
Structural And Functional Properties Of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$188,623.00
Summary
Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protei ....Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protein tyrosine phosphatases, SHP-1 and SHP-2. We would therefore consider PECAM-1 as a new member of an emerging Ig-ITIM superfamily. Members of the Ig-ITIM gene family have both inhibitory-non-inhibitory receptors which upon ligation of specific receptors can globally stimulate or inhibit cellular activation in the context of B cells, Tcells, mast cells , endothelial cells or platelets. Balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease, to provoke immunological memory from vaccination and to dampen the extent and duration of platelet activation. Our investigations are focussing on the isolation and functional characterisation of PECAM-1 family members to define their role in regulating cell signaling pathways in vascular and haematopoietic cells. We predict that PECAM-1 has numerous undefined family members that exist as multiple isoforms as a product of separate genes, alternative splicing of discrete exons and single point mutations giving rise to conservative and non-conversative amino acid changes. The longer term potential of this study is to provide knowledge for understanding the structural and functional roles of PECAM-1 isoforms in physiological cells in health and disease. This knowledge could then be applied to provide targets for novel therapeutic interventions in the clinical management of autoimmune disease, humoral and inflammatory responses.Read moreRead less
Inhibition Of Endothelial Cell Adhesion Molecule Expression By High Density Lipoproteins
Funder
National Health and Medical Research Council
Funding Amount
$80,550.00
Summary
It is well known that high levels of cholesterol in blood cause coronary heart disease. However, it is also known that not all of the blood cholesterol is bad. If it is carried in particles called low density lipoproteins or LDLs it causes heart disease. But if it is carried in other particles known as high density lipoproteins or HDLs it does not. In fact, it is now well known that HDLs actually protect against the development of coronary heart disease. There are two main actions of HDLs that c ....It is well known that high levels of cholesterol in blood cause coronary heart disease. However, it is also known that not all of the blood cholesterol is bad. If it is carried in particles called low density lipoproteins or LDLs it causes heart disease. But if it is carried in other particles known as high density lipoproteins or HDLs it does not. In fact, it is now well known that HDLs actually protect against the development of coronary heart disease. There are two main actions of HDLs that contribute to their ability to protect. Firstly, they are known to drain cholesterol out of coronary arteries. We have recently shown that they have a second action. The end result of this second action is a slowing down of the entry into coronary arteries of cells called monocytes that are necessary for the development of the atherosclerosis that causes the heart disease. This project is concerned with this ability of HDLs to slow down the development of atherosclerosis by the second action. We have found that this second action of HDLs is influenced by the type of fats they carry. We propose now to investigate the mechanism by which different fats influence this action of HDLs with a view to devising new strategies for the prevention of heart disease.Read moreRead less