In this study, mouse models of disease will be used to determine the mechanisms by which the proinflammatory molecule called MIFpromotes the development of insulin resisitance and type 2 diabetes. We will also test whether therapeutic blockade of MIF can prevent the progression of disease in mice with established type 2 diabetes. Studies on tissue samples obtained from human patients will be used to confirm the human relevance of these findings.
Macrophage Migration Inhibitory Factor (MIF) And P53 In Rheumatoid Arthritis .
Funder
National Health and Medical Research Council
Funding Amount
$333,055.00
Summary
Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is characterised by severe inflammation and destruction of joints resulting in significant health problems. The lining tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of inflammatory cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute significantly to joint damage by invading cartilage and bone an ....Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is characterised by severe inflammation and destruction of joints resulting in significant health problems. The lining tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of inflammatory cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute significantly to joint damage by invading cartilage and bone and allowing inflammatory cells to reach these areas. The abnormal growth of these cells has been related to the malfunction of certain genes that usually restrain abnormal growth. These genes called tumour suppressor genes are known to be damaged in joint lining cells derived from RA. The best known of these abnormal tumour suppressor genes is called p 53. The product of the p53 gene, the p 53 protein, is particularly important in slowing down the growth of cells. The applicant has recently shown that an inflammatory product called MIF is released in large quantities by joint lining cells in RA. Previous studies by the applicant have shown that blocking MIF using an antibody almost completely prevents arthritis development in a rat model. These studies indicate that MIF is likely to be an important contributor to disease in RA. Recent preliminary studies in the applicant s laboratory have shown that MIF can decrease p53 levels in joint lining cells from RA patients and also that MIF can increase the growth rate of these cells. These preliminary data indicate that MIF may contribute significantly to disease in RA by overriding control of normal cell growth by p53. Confirmation and full exploration of the regulation of p53 expression and function by MIF may highlight a novel way to treat the excessive growth and invasion by joint lining cells which characterises RA.Read moreRead less
Macrophage Migration Inhibitory Factor (MIF): Pathological And Therapeutic Significance In Post- Infarct Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$547,577.00
Summary
Ischemic heart injury mediated by the inflammatory response has a significant impact on the prognosis. MIF is a central factor mediating and amplifying the inflammatory response but its role in heart disease remains largely untested. This project will study, for the first time, the crucial role of MIF in ischemic heart disease and will establish important experimental evidence for developing new anti-inflammation therapeutic strategies against ischemic heart injury.
Phagocytic Clearance And Immune Activation In Malaria
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
Macrophage white blood cells clear malaria infected cells by eating them, by three routes- by recognising ANTIBODIES or COMPLEMENT on the cell surface, or by the cell BINDING directly to the macrophage. Each has different results, such as amounts of cytokines produced. Cytokines clear malaria; in excess they can cause fatal immune pathology. We will investigate how variations in amount of antibody and complement and route of uptake of malaria infected cells might determine malaria outcome.
Kidney Injury As A Determinant Of Macrophage Phenotype And Efficacy For Treating Chronic Kidney Disease (CKD)
Funder
National Health and Medical Research Council
Funding Amount
$548,341.00
Summary
Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or tranplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Macrophage infiltration of kidneys is characteristic of C ....Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or tranplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Macrophage infiltration of kidneys is characteristic of CKD, and it has been assumed that macrophages cause damage. However, we have shown that certain types of macrophages can reduce kidney damage. This project will explore whether macrophage type can be switched from that causing damage to that reducing injury, with the aim of using this approach to treat CKD.Read moreRead less
Macrophages are important cells at the front-line of immunity where one of their main roles is to release anti-bacterial proteins. We will study the macrophage molecules, subcellular organelles and pathways that help to release these proteins to kill bacteria and fight infection. Our studies will identify new cellular targets for boosting immunity and treating inherited diseases with defective macrophage function.
After infection with viruses, parasites and bacteria the protein SerpinB2 becomes very abundant in macrophages, which are white blood cells involved in inflammation. Unfortunately, what this protein is doing is very unclear. We have found that macrophage SerpinB2 dampens the responses of other immune cells. This grant aims to determine how this is achieved and thereby help resolve the role of this protein in a number of diseases such as cancer, lupus, asthma and pre-eclampsia.
This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the DNA of infectious agents such as bacteria. This has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define how the recognition system for foreign DNA works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We ....This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the DNA of infectious agents such as bacteria. This has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define how the recognition system for foreign DNA works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We are investigating how a key protein that is required for these responses functions and what genes it turns on. The type of immune responses initiated by foreign DNA may be useful in treatment of allergies and cancer, and for improving vaccinations.Read moreRead less