The Role Of Proteinase Inhibitor 9 In Cytotoxic Lymphocyte Function
Funder
National Health and Medical Research Council
Funding Amount
$820,136.00
Summary
Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are a ....Cytotoxic lymphocytes eliminate virus-infected or cancerous cells from the body. This is achieved by the release of powerful cytotoxins that kill the abnormal cell. Unless carefully targeted these cytotoxins can damage surrounding normal tissue or the cytotoxic lymphocyte itself, and lead to autoimmune disease. One of the most important cytotoxins is a protease called granzyme B. We have discovered a natural inhibitor of granzyme B that is present in cytotoxic cells and testis. Our studies are aimed at understanding the role of the inhibitor in human immune and reproductive function. We will also design and evaluate synthetic compounds based on the natural inhibitor that will enable us to easily measure granzyme B levels and control its activity.Read moreRead less
Proteinase Inhibitor 6: A Multifunctional Intracellular Serpin
Funder
National Health and Medical Research Council
Funding Amount
$217,435.00
Summary
We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we hav ....We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we have evidence that inhibitor regulates other, unidentified, proteases. The purpose of this grant is to identify these proteases, and to elucidate the physiological significance of the inhibitor by studying mice that lack it.Read moreRead less
Regulation Of Lysosomal Proteases By The Intracellular Serpin, PI-6.
Funder
National Health and Medical Research Council
Funding Amount
$152,500.00
Summary
All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell a ....All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell act as stress sensors and participate in initiating programmed cell death. In particular, it appears that degradative enzymes (proteases) released under stress from waste disposal-recycling organelles (lysosomes) can induce death. This may occur in settings such as infection or cardiovascular disease (e.g. stroke). As part of a defence mechanism to counter low level release of these lysosomal proteases, we propose that some cells produce inhibitors called serpins. In preliminary work we have shown that particular serpins do indeed inactivate a subset lysosomal proteases. We propose to study the role of these serpins in protecting cultured cells from stress and the effects of lysosomal protease release. In addition, we will use mice lacking one of these serpins to evaluate its importance in the physiological response to stresses such as bacterial and viral infection, tumor formation and stroke.Read moreRead less