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.
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
Detection Of Metastases In Sentinel Nodes From Patients With Breast Cancer Using Proton Magnetic Resonance Spectroscopy
Funder
National Health and Medical Research Council
Funding Amount
$186,372.00
Summary
The objective is to develop magnetic resonance spectroscopy (MRS) for the rapid and accurate intra-operative detection of cancer cells in sentinel lymph nodes from breast cancer patients. Accurate intra-operative diagnosis of cancer in lymph nodes will enable informed decisions to be made regarding surgery and therapy and reduce the morbidity associated with complete clearance of axillary nodes. Using current histopathological techniques (frozen section) this is not possible. Proton MRS can dete ....The objective is to develop magnetic resonance spectroscopy (MRS) for the rapid and accurate intra-operative detection of cancer cells in sentinel lymph nodes from breast cancer patients. Accurate intra-operative diagnosis of cancer in lymph nodes will enable informed decisions to be made regarding surgery and therapy and reduce the morbidity associated with complete clearance of axillary nodes. Using current histopathological techniques (frozen section) this is not possible. Proton MRS can detect chemicals in malignant cells in lymph nodes with a greater sensitivity than histology and can detect micrometastases in 20 minutes. The MR diagnostic information can be obtained from fine needle biopsies (FNB) making the technique eminently suitable for rapid intra-operative diagnosis. The FNB technique has been shown to be a rapid and accurate method for the assessment of breast lesions, distinguishing benign lesions and invasive cancer with a sensitiviy and specificity of 95% and 96%, respectively. Here we propose to evaluate the use of MRS for the rapid and accurate assessment of sentinel nodes from breast cancer patients. Two blinded studies will be conducted comparing the MRS chemical fingerprints with serial section histopathological data. To evaluate the clinical significance of the MRS diagnosis, all patients will be entered into a prospective study correlating the MRS data with recurrence of disease within 3 and 5 year periods.Read moreRead less
The Role Of Melanoma Tumour Antigen P97 (Melanotransferrin) In Melanoma Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$563,242.00
Summary
The Role of Melanoma Tumour Antigen p97 (Melanotransferrin) in Melanoma Tumourigenesis Melanotransferrin (MTf) is a homologue of the iron transport protein, transferrin, and was one of the first well characterised melanoma tumour antigens. Our published studies have shown that MTf plays an important role in melanoma tumourigenesis in vivo. In this proposal, we will assess if it is associated with melanoma progression in patient samples and examine its role in melanoma growth and metastasis.
This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflamma ....This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflammatory events. They are known to be important in allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100 protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this project will provide new knowledge of chronic inflammatory processes and could result in designing novel strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and infection.Read moreRead less
Regulation Of 14-3-3 Monomerisation Controls Cell Life/death Fate
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
14-3-3 proteins are becoming increasingly recognised as major multifunctional proteins that control key aspects of normal and pathological processes. Although initially viewed as inert components of signalling, we have now recognised for the first time that these are very dynamic proteins that can be regulated. Our main aim is to understand the regulatory mechanisms controlling the different dynamic forms of 14-3-3 and how each form in turn controls the process of life and death.
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
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.
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