Peptidase Inhibitor 16: A New Biomarker For Human Treg
Funder
National Health and Medical Research Council
Funding Amount
$391,262.00
Summary
As autoimmune diseases including type 1 diabetes and IBD are on the increase, there is still great need for novel diagnostic or therapeutic molecules. We have discovered a novel role for a protein called PI16, which we believe is a biomarker for natural regulatory T cells. These cells police the immune system, preventing inappropriate immune responses such as those that cause autoimmune diseases. This project will confirm its suitability for use as a diagnostic or therapeutic biomarker.
Macrophage-regulated Tissue Remodelling In Endometrial Receptivity For Embryo Implantation And Pregnancy Success
Funder
National Health and Medical Research Council
Funding Amount
$456,779.00
Summary
Infertility and recurrent miscarriage affect 60-80 million couples globally, including 15% of couples in Australia. Moreover, 1 in 6 pregnancies is affected by pre-eclampsia, low birth weight or preterm labour. Infertility and other pathologies in pregnancy often result from failure of the maternal tissues to adequately support embryo implantation and development of the placenta, leading to insufficient nutritional support of the developing fetus. We have discovered in mice that disruption in th ....Infertility and recurrent miscarriage affect 60-80 million couples globally, including 15% of couples in Australia. Moreover, 1 in 6 pregnancies is affected by pre-eclampsia, low birth weight or preterm labour. Infertility and other pathologies in pregnancy often result from failure of the maternal tissues to adequately support embryo implantation and development of the placenta, leading to insufficient nutritional support of the developing fetus. We have discovered in mice that disruption in the populations of immune cells called macrophages within the uterine endometrial lining can reduce the receptivity of the endometrum to embryo implantation, and can lead to fetal growth retardation and impaired health after birth. The purpose of this project is to delineate the precise functions of macrophages in interacting with other cells in the endometrium to facilitate attachment of the embryo, its invasion into maternal tissues, and its access to an adequate blood supply as the placenta develops during early pregnancy. We will employ state of the art experimental strategies including genetic models to deplete endometrial macrophage populations in mice, and will then study the implications for changes in endometrial tissue structure and function. Furthermore we will investigate the long term consequences of early macrophage perturbations for the fetus and neonate after birth. This study will improve our understanding of how determinants of macrophage function such as infection and inflammatory conditions, male factors, nutrition and stress can impair fertility and compromise optimal pregnancy outcome in humans.Read moreRead less
Bacterial Outer Membrane Vesicles As Immunomodulatory Agents In Helicobacter Pylori Infection
Funder
National Health and Medical Research Council
Funding Amount
$306,510.00
Summary
Chronic inflammation of the stomach is a hallmark of Helicobacter pylori infection, and is a precursor to peptic ulcer disease and cancer. Like many other bacteria, H. pylori sheds spherical blebs from its surface. These blebs bind to stomach cells in vitro and have been found in stomach biopsies of H. pylori-infected subjects. The aims of the work are to investigate the mechanisms whereby H. pylori blebs enter and disseminate within host cells, and how this may contribute to inflammation.
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
A Study Of The Molecular Epidemiology And Virulence Determinants Of Enterovirus 71 Strains From The Asia-Pacific Region
Funder
National Health and Medical Research Council
Funding Amount
$286,325.00
Summary
In this study, we aim to understand the reasons for the emergence of epidemics of severe neurological disease due to enterovirus 71 (EV71) in young children of the Asia-Pacific region since 1997, and to develop strategies for disease prevention. EV71 is a human enterovirus closely related to the polioviruses. Most infections with EV71 are trivial, however, they may occasionally result in severe disease, including brainstem encephalitis with a high mortality and acute flaccid paralysis similar to ....In this study, we aim to understand the reasons for the emergence of epidemics of severe neurological disease due to enterovirus 71 (EV71) in young children of the Asia-Pacific region since 1997, and to develop strategies for disease prevention. EV71 is a human enterovirus closely related to the polioviruses. Most infections with EV71 are trivial, however, they may occasionally result in severe disease, including brainstem encephalitis with a high mortality and acute flaccid paralysis similar to poliomyelitis. There has been a large increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997, including a large epidemic in Perth, Western Australia in 1999. These epidemics have resulted in many deaths and cases of severe neurological disability. In view of the severity of EV71 neurological disease and the lack of effective treatments, our research effort needs to focus on prevention through public health surveillance and vaccine development. The major aims of our study are two-fold: 1. To study the origin and evolution of EV71 in the Asia-Pacific region using molecular techniques and to use this information to implement surveillance in Australia and Southeast Asia. It is anticipated that improved surveillance will provide early warning of impending epidemics. 2. To understand the molecular basis of virulence of EV71, with emphasis on the ability of virus to cause severe disease of the central nervous system. This study will have two goals: a. To identify the human cellular receptor of EV71. The ultimate goal of this research will be the development of a small animal model of EV71 encephalitis by constructing a transgenic mouse expressing the human cellular receptor for EV71. b. To construct an infectious cDNA clone of EV71 and to develop genetically defined attenuated strains by mutagenesis of the infectious clone. Mutant strains of EV71 will be tested for replication and virulence in newborn mice and in human neuroblastoma cells.Read moreRead less
Mechanisms Of Dendritic Cell-induced T-cell Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$314,773.00
Summary
Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. Thes ....Autoimmune diseases constitute a significant medical problem in the developed world and are increasing in incidence. Many control mechanisms exist in the body, but in people with genetic suceptibility to autoimmune disease, the mechanisms fail and the body's immune sytem attacks normal tissues or organs. We have developed a new approach to using the cells which train the immune system to re-educate the cells that would otherwise attack normal healthy tissues in autoimmune-prone individuals. These cells (dendritic cells) are genetically modified to express the molecular targets of the autoimmune response. This in turn switches off the response to these targets. In this project we will explore how these cells can be used to turn off cells of the immune system and if cells of the immune system in turn control the dendritic cell's ability to do this.Read moreRead less
The Role Of 14-3-3 Proteins In Regulating The Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
The immune response is the body's defense system. It's malfunction leads to many diseases such as immune deficiency, asthma and cancer. Thus, it is important to find genes controlling immunity. Significantly, mammals have amazing similarities with flies, in terms of genes controlling immunity. We have found a new regulator of fly immunity and will define how this gene functions in the immune system. This project will identify potential points of intervention for treating immune system disorders.
Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~50 ....Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~500 deaths and over 20,000 registered infections since its emergence in North America in 1999, including 223 deaths and 9122 infections in 2003 alone. Recent studies with DEN indicated that flaviviruses may interfere with early steps of IFN-signalling pathway. The type I Interferon (IFN) response is the first line of defence against viral infections and many viruses have developed different strategies to counteract this response in order to ensure their survival in the infected host. In this grant we seek to exploit our extensive understanding of the molecular biology of KUN virus and the contrasting behaviour of KUN and NY WN viruses to gain an understanding of the role of flavivirus-mediated suppression of host anti-viral IFN response in virus-host relationships and its importance in determining virus virulence.Read moreRead less
Drugs are broken down in the body by the process of metabolism. Metabolism is important as both a detoxification and elimination mechanism, and determines dose rate for chronically administered drugs. Many drugs are metabolised by a reaction called glucuronidation. We will characterise the various components of the glucuronidation reaction in an integrated manner in order to understand and predict factors that influence an individual's capacity to metabolise drugs and other chemicals.
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