The Role Of Mal In Toll-like Receptor Signal Transduction Of The Pro-inflammatory Response.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune syste ....Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune system. Dysregulation of the pro-inflammatory response can lead to sepsis. Recently, the mammalian receptor for LPS was found to be Toll-like receptor (TLR)-4, the activation of which activates a signal transduction pathway that initiates the pro-inflammatory response. We have previously shown a key role for an adapter protein called Mal in mediating signal transduction pathways upon activation of TLR-4. Interaction of Mal with a key signal transduction mediator called TRAF6 has been shown to induce the activation of the pro-inflammatory response. Furthermore, Mal has been found to undergo degradation which may indicate a means of regulating the continued activation of the pro-inflammatory pathway. This research program will investigate the role of Mal in mediating signal transduction in TLR activated macrophages, key responsive cells of the innate immune system to microbial infection. A greater understanding of these processes will assist in the development of therapeutics to alleviate the consequences of microbial-induced inflammation, including chronic inflammatory diseases and sepsis.Read moreRead less
Competition For Polarity Influences Lymphocyte Signaling And Function
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
Infectious diseases caused by viruses and bacteria remain a significant health problem. CD46 is a protein on the surface of human cells that is used by a number of viruses and bacteria to enter and infect host cells. Through binding to the CD46 protein, viruses and bacteria can induce changes in immune cells, such as T lymphocytes, that affect the way our immune system responds to infection. For example, immunosuppression induced by infection with measles virus is the primary cause of the mortal ....Infectious diseases caused by viruses and bacteria remain a significant health problem. CD46 is a protein on the surface of human cells that is used by a number of viruses and bacteria to enter and infect host cells. Through binding to the CD46 protein, viruses and bacteria can induce changes in immune cells, such as T lymphocytes, that affect the way our immune system responds to infection. For example, immunosuppression induced by infection with measles virus is the primary cause of the mortality and morbidity associated with the disease, and is a phenomenon that is poorly understood. However, there is evidence to suggest that the interaction between measles-infected cells with CD46 on the immune cells is partly responsible for the immunosuppression observed. Our laboratory has recently found that binding of CD46 (by antibody or measles antigen) on immune cells provides a signal to the cell to change its polarisation state (the way proteins are distributed within the cell) and impairs their ability to recognize and kill target cells, and become activated. These observations indicate a new paradigm by which competition of receptor signals for polarization determines signalling outcomes and provides a possible mechanism for how pathogens that bind CD46, such as measles, subvert normal immune cell communication and induce immunosuppression. This proposal aims to investigate the mechanisms behind the effect of polarising signals on immune cells, and will specifically use CD46 and measles virus as a model. The outcomes of this study will define new paradigms in lymphocyte biology and dissect the key pathways that underpin how CD46 influences immune outcome in response to infection.Read moreRead less
Dendritic Cell-mediated Induction Of T Cell Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$654,725.00
Summary
Australia has some of the highest rates of immune-mediated diseases in the world. These diseases include autoimmune, allergic and inflammatory conditions. We will use a mouse model to study how dendritic cells can prevent the onset of these conditions by inactivating the immune cells that cause them. Our findings will aid in understanding why these diseases develop and how they may be prevented and treated.
Investigation Of Cellular Abnormalities And Synapse Formation In DOCK8 Immunodeficiency
Funder
National Health and Medical Research Council
Funding Amount
$318,284.00
Summary
Why do some people get allergies? Or serious infections? To investigate this we will study mice and humans with a mutation in the DOCK8 gene. People with mutations in the DOCK8 gene get Hyper-IgE Syndrome and develop severe viral infections of the skin as well as allergic disease. By investigating how DOCK8 works in the cells of the immune system, we hope to understand why these infections and allergies occur and find out why these problems can also happen in those without this specific genetic ....Why do some people get allergies? Or serious infections? To investigate this we will study mice and humans with a mutation in the DOCK8 gene. People with mutations in the DOCK8 gene get Hyper-IgE Syndrome and develop severe viral infections of the skin as well as allergic disease. By investigating how DOCK8 works in the cells of the immune system, we hope to understand why these infections and allergies occur and find out why these problems can also happen in those without this specific genetic defect.Read moreRead less
Taking The First Steps From Promise To Product: Exploration Of The Newly Discovered Interleukin 37 Receptor Complex And Its Signaling Pathways
Funder
National Health and Medical Research Council
Funding Amount
$694,623.00
Summary
Cytokines are messenger proteins used by most cells of the body. They function as master regulators of many biological processes and as such play an important role in a wide spectrum of diseases. Anti-inflammatory cytokines attenuate the potentially destructive force of other cytokines and the immune system as a whole, and are therefore coveted as drug targets. We discovered the formidable anti-inflammatory properties of IL-37 and will now explore how these activites can be utilised in clinical ....Cytokines are messenger proteins used by most cells of the body. They function as master regulators of many biological processes and as such play an important role in a wide spectrum of diseases. Anti-inflammatory cytokines attenuate the potentially destructive force of other cytokines and the immune system as a whole, and are therefore coveted as drug targets. We discovered the formidable anti-inflammatory properties of IL-37 and will now explore how these activites can be utilised in clinical medicine.Read moreRead less
Immune Imprinting By Nanoparticles And Vaccines: New Principles And Translation Into The Clinic
Funder
National Health and Medical Research Council
Funding Amount
$631,010.00
Summary
Vaccines require adjuvants to be effective. Despite decades of research there is only one adjuvant approved for broad use in humans. Based on our prior findings I will engage new principles in nanotechnology, and deepen understanding of immune imprinting in various organs of the body including the lung, to develop 2nd generation broadly useful nanoadjuvants able to effectively treat cancer and malaria.
Roles Of Signalling In The Control Of Immune System Development, Function And Pathology
Funder
National Health and Medical Research Council
Funding Amount
$737,936.00
Summary
This research focuses on the function of the NF-?B and MAP kinase biochemical pathways in immune cells. Both pathways regulate gene expression controlling the development, division, viability and function of immune cells. Consistent with these roles, impaired regulation of these pathways contributes to many immune related diseases. My goal is to utilize information learnt about these pathways and apply it to developing therapies for treating diseases afflicting the immune system.