Understanding The Role Of Nociceptin In PMNL-mediated Inflammation In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
This work will study the role of a type of protein in white blood cell movement into tissues, a process called inflammation. The outcome of this work may lead to the development of molecules which control this movement of white blood cells more specifically than existing therapeutics. Such inhibitors would potentially be useful as anti-inflammatory agents in a range of human diseases.
Membrane TNF And Lymphotoxin Control Of Chemokine Induction And Inflammation In Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent wide ....Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent widespread infection that would cause illness in the host. Activated T lymphocytes that recognise TB-infected macrophages circulate in blood, are recruited from blood capillaries into the lung, migrate through the tissue and co-localise with infected macrophages. Soluble molecules (cytokines and chemokines) are known to provide the signals that direct cell migration and activation events. This study will investigate in detail cytokines and chemokines that are involved, the cells that produce then and where these cells are located in the lung. We recently showed that tumour necrosis factor (TNF), and the related cytokine lymphotoxin (LT), are essential for lymphocyte migration through the lung. These belong to a family of related molecules that signal through the same panel of receptors and regulate chemokine expression and inflammation. In this study we will use genetically manipulated mice that lack TNF. LT or other family members or that express only membrane-bound TNF to study how each affects production of different chemokines, chemokine receptors and other molecules. Since there are at least 50 known chemokines and 17 chemokine receptors we will use microarray technology to simultaneously screen changes in expression of several thousand genes and laser microdissection to study cells from different location in infected lungs. Understanding signals necessary to direct T cells into granulomas may facilitate new treatments to prevent TB reactivation disease.Read moreRead less
Relationship Between Cell-cell Interactions And Disease Severity In Patients With Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$545,183.00
Summary
Severe malaria is a collection of disease complications that leads to about 2 million deaths each year worldwide. Young children in Africa and young adults in several parts of South-East Asia are particularly affected. Travellers to these regions are also at considerable risk. One of the most dangerous complications of malaria is when the brain becomes affected, which is called cerebral malaria. We still do not understand enough about the changes that link the parasite circulating in the blood w ....Severe malaria is a collection of disease complications that leads to about 2 million deaths each year worldwide. Young children in Africa and young adults in several parts of South-East Asia are particularly affected. Travellers to these regions are also at considerable risk. One of the most dangerous complications of malaria is when the brain becomes affected, which is called cerebral malaria. We still do not understand enough about the changes that link the parasite circulating in the blood with the devastating disturbance of brain function that causes death in some people who develop cerebral malaria. In this project we will investigate some new ideas about how cerebral malaria develops. We will perform a detailed study of brain tissue taken from victims of cerebral malaria and compare the observations with similar ones in children who died of other causes. Then we will work with an experimental model we have developed, in which we put together in culture flasks the various types of cell that are found in the brain lesions in people who die from cerebral malaria. Our aim is to identify some new therapeutic targets for later use in treatment of cerebral malaria patients.Read moreRead less
Persistent Particles And Monocyte/macrophage Function
Funder
National Health and Medical Research Council
Funding Amount
$356,232.00
Summary
The project studies how a type of white blood cell interacts with damaged tissue at a site of inflammation, such as an occluded vessel or a brain plaque, and also with immunological adjuvants. It is believed that the nature of the material to be removed is critical in determining the effect on the white blood cell such that it can stay longer at the site and cause more damage or stimulate more immunity, respectively. The ultimate goal is to understand the cellular biochemistry responsible to hel ....The project studies how a type of white blood cell interacts with damaged tissue at a site of inflammation, such as an occluded vessel or a brain plaque, and also with immunological adjuvants. It is believed that the nature of the material to be removed is critical in determining the effect on the white blood cell such that it can stay longer at the site and cause more damage or stimulate more immunity, respectively. The ultimate goal is to understand the cellular biochemistry responsible to help diseases, such as atherosclerosis and Alzheimer's disease, and to improve the quality of human adjuvants.Read moreRead less
Cell Migration And Granuloma Formation In The Expression Of Protective Immunity Against Tuberculosis In The Lung
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to th ....Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to the lung, migrate into lung tissue and surround infected lung macrophages forming granulomas. We have identified mice that progress to TB disease early after infection (early progressor strains) and another strain that progresses later (late progressors). In the early progressors, lymphocytes are not as efficiently recruited to the lung and do not form the tight granulomas seen in late progressor strains. We plan to make a detailed comparison of these two strains looking at differences in cell-membrane molecules and the soluble messenger molecules (cytokines and chemokines) that provide the signals that attract cells to the lung and direct them to surround infected lung macrophages. By comparing events in early and late progressor strains we will find which molecules are required for initial and long-term containment, and which events lead to breakdown of granulomas and reactivation of disease. In addition, we recently showed that one cytokine, tumour necrosis factor (TNF), is essential for cell migration through the lung. By comparing normal mice with mice deficient in TNF we will study the downstream effects regulated by TNF, particularly the chemokine messengers that direct cell movement into granulomas. By identifying the molecules and cells required to control TB we plan to design improved vaccines to prevent TB infection and improved treatments to prevent disease reactivation.Read moreRead less
Procoagulant Expression In The Antiphospholipid Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
This study proposes to investigate how white blood cells contribute to clotting that occurs in patients with an immune disorder called the Antiphospholipid Syndrome. This condition is more common than is generally known, and accounts for about one fifth of clots in the legs and about one third of strokes that occur in young people. It is also a common cause of miscarriages. The study focuses on how activation of the immune system, and inflammation interact to make certain white blood cells expre ....This study proposes to investigate how white blood cells contribute to clotting that occurs in patients with an immune disorder called the Antiphospholipid Syndrome. This condition is more common than is generally known, and accounts for about one fifth of clots in the legs and about one third of strokes that occur in young people. It is also a common cause of miscarriages. The study focuses on how activation of the immune system, and inflammation interact to make certain white blood cells express a molecule called Tissue Factor, which initiates blood clots.Read moreRead less
Cytokine And Macrophage Determinants Of Pulmonary Inflammation During Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$455,899.00
Summary
Tuberculosis (TB) infects 33% of the world, causing over 2 million deaths per year. TB disease causes damaging lung pathology and new therapies to treat the infection and moderate inflammation are urgently required. TNF is essential for immunity to TB, acting to modulate inflammation. This grant will determine how soluble and membrane- bound TNF regulate the cellular and cytokine control of TB pathology and may lead to new therapies to limit inflammation in TB and other inflammatory diseases.
Endothelial Cell Membrane Stabilisation: Deciphering Protective Mechanisms Against Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$358,319.00
Summary
Each year 3.2 billion people are exposed to the threat of malaria, resulting in about 2 million deaths annually. Deaths due to malaria often result from complications that affect the brain; this is called cerebral malaria . We still do not understand enough about the changes that cause cerebral malaria, so this project will investigate some new ideas about how cerebral malaria develops. Our aim is to identify new therapeutic targets that could help people survive this fatal disease.