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
The Role Of Cellular Microdomains In G-protein Coupled Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$385,297.00
Summary
Molecules communicate with cells by attaching to proteins called receptors on the outside of cells, and triggering a series of events inside the cell. These events initially include the assembly of multiple proteins at the cell surface. This project will examine the formation of receptors and other proteins into these ‘communication complexes’. This will provide novel targets for more selective drug development.
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how each of these components, the stimulating agent, the receptor and G protein, works in order to understand how the cells respond to various chemical signals. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. Understanding what actually is the role of these new players, and how they team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less