Structural Basis For Inhibition Of Malaria Invasion By Targeting The Apical Membrane Antigen Of Plasmodium Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
3 million children die every year from malaria infections. A leading vaccine candidate is a protein from the malaria parasite called AMA1. Humans that have been infected with malaria make antibodies to this protein which can kill parasites, however little is known about how this occurs. We aim to identify regions of the protein that generate antibodies that prevent malaria parasites from invading human cells and help in the search for a vaccine against malaria.
The Effect Of Follicular Helper T Cells (TFH) On AID Regulation And Selection Of High Affinity Germinal Centre B Cells.
Funder
National Health and Medical Research Council
Funding Amount
$430,964.00
Summary
An integral component of an immune response to foreign pathogens is the production of antibodies by B cells. However, if antibodies react to self-antigens (human molecules rather than bacteria or viruses) they may also cause autoimmune diseases such as lupus. This research project is investigating the mechanisms that control antibody generation by B cells, and how these are dysregulated in autoimmune diseases, such as lupus.
Role Of Complement Factor H And Related Proteins In Regulating Complement Activation And Microbial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
A group of proteins in blood called Complement are activated in the presence of foreign cells or organisms and this generally results in their destruction. It is important to direct this destructive activity against foreign and not self tissue. This is achieved by a further family of proteins, including factor H, which regulate complement activity and how these proteins work is the principal focus of this project. There are many diseases in which damage results from inadvertent complement damage ....A group of proteins in blood called Complement are activated in the presence of foreign cells or organisms and this generally results in their destruction. It is important to direct this destructive activity against foreign and not self tissue. This is achieved by a further family of proteins, including factor H, which regulate complement activity and how these proteins work is the principal focus of this project. There are many diseases in which damage results from inadvertent complement damage and the regulatory proteins have therapeutic potential in this area. In addition many bacteria and other microorganisms, which should be destroyed by complement, escape by binding regulatory proteins. Understanding how this is achieved may reveal new targets for vaccine development. Knowledge of how the production of factor H and related proteins will help understand how inflammation occurs and how it might be controlled.Read moreRead less
Structure And Function Of Receptors For IgG (FcgammaR)
Funder
National Health and Medical Research Council
Funding Amount
$772,315.00
Summary
We are investigating one of the most important receptor families of inflammatory white blood cells - so called Fc receptors. These are critically important in resistance to infection. Unfortunately they are also crucial in tissue destruction in autoimmune diseases such as rheumatoid arthritis. We will determine how these receptors trigger inflammation and use this information for the development of new drugs to treat rheumatoid arthritis and lupus.
Monoclonal Antibodies Targeting Plasma Cells As Novel Therapeutic Agents And Diagnostic Tools
Funder
National Health and Medical Research Council
Funding Amount
$199,275.00
Summary
We have a new tool to identify a very rare immune cell type. This cell makes antibodies, powerful and exquisitely specific proteins that fight infection. In health, antibody-producing cells are beneficial, but in disease (rheumatoid arthritis, lupus and myeloma), these cells cause disease or death. Antibody-producing cells are long-lived. We have no means to specifically deplete them. We are developing reagents to identify and deplete antibody-producing cells to use as novel therapeutic agents.
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
Molecular Dissection Of Cytokine-mediated Regulation Of Human B-cell Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$119,314.00
Summary
Interleukin 21 is a molecule which activates B cells. Defects in this pathway cause immunodeficiency where individuals cannot make antibodies, while constant activation has been reported in mouse models of autoimmunity. Examining these pathways will shed light on the causes of human immune disease, and may reveal molecules that could be targeted for the treatment of immunodeficiency and autoimmunity. Amplification of normal immune responses could lead to the development of improved vaccines.
Antibodies are the main line of defence the immune system utilises to target viruses and bacteria that invade our body. Raising the level of antibodies can therefore offer effective protection against disease. However, as antibodies cannot be taken orally (as a tablet) they have to be injected into the blood stream. We aim to overcome this limitation by generating antibodies that survive the passage through the stomach, allowing us to target conditions such as Crohn's disease.
Inflammatory disorders a variety of pathologies, besides septicemia, infections and non-infective diseases, also are implication in metabolic disorders, such as type 2 diabetes (T2D) and hypercholesterolemia . Activin A is a protein that has important effects in inflammatory disorders. Because T2D and hypercholesterolemia have inflammatory characteristics and activin A has important effects in inflammatory disorders, it merits studying the links between activin A, T2D and hypercholesterolemia.
Cell Division And The Regulation Of Immunoglobulin Switch Recombination At The Molecular Level
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
The B lymphocyte is an important cell in the immune response as it generates protective antibody against invading pathogens. The effectiveness of an antibody response partly depends on the type of antibody made (there are eight different types). This attribute alters as the immune response progresses in a poorly understood and highly complex way. However, our recent studies have revealed a simple underlying order that can be dissected using new methods. The key to the underlying simplicity is a ....The B lymphocyte is an important cell in the immune response as it generates protective antibody against invading pathogens. The effectiveness of an antibody response partly depends on the type of antibody made (there are eight different types). This attribute alters as the immune response progresses in a poorly understood and highly complex way. However, our recent studies have revealed a simple underlying order that can be dissected using new methods. The key to the underlying simplicity is a cell division clock used to relate and promote cell changes. Here we intend to apply this new concept and the new methods to dissecting the molecular events associated with linking division to the changing properties of antibody selection. Our aim is to accurately model the process of changing antibody types at both the molecular and whole tissue levels. These studies will give us new insights into how the immune response may be directed to make the most appropriate (effective) response during infection and vaccination.Read moreRead less