The long-term objective of our research is to determine the mechanisms by which mast cells regulate the host response to bacterial lung infections and to be able to modify how mast cells coordinate this response in ways that benefit the host. Recently, we made the discovery that the mast cell protease dipeptidyl peptidase I (DPPI) contributes to death of the host from septic peritonitis and that it appears to do so by regulating levels of mast cell IL-6. This suggests that mast cell DPPI, or other mast cell proteins regulated by DPPI, modify the host response to bacterial infection in ways that harm the host. Our central hypothesis is that: Mast cell proteases and cytokines coordinate lung defense against bacterial infections. While coordinating this defense, some of these mediators protect the host and improve survival while others harm the host and worsen survival.
Specific aims are: #1. To determine the mechanism by which mast cell DPPI modulates the host response and survival from bacterial lung infections. This will be accomplished by applying a new method for creating mast cell-specific knockout mice and determining the physiologic mechanism for survival following inoculation with Klebsiella pneumoniae. #2. To define mechanisms by which mast cell proteases regulate cytokine levels during bacterial infections. We will test whether mast cell proteases hydrolyze cytokines by incubating cytokines with purified DPPI, tryptase or chymase and identifying cleavage products. Protease mediated cytokine production will be studied by measuring cytokines released by specific lung cells in response to DPPI, tryptase or chymase. #3. To determine whether mast cell TNF-alpha, IL-6, or IL-10 modulate the host response and survival from bacterial lung infections. We will use mast cell-specific-TNF-alpha, -IL-6, or -IL-10 knockout mice to test if mast cell sources of these cytokines play important roles in host defense. By understanding how specific mast cell mediators regulate host defense, we will gain greater insight into how these cells influence host survival. This knowledge can then be applied to the development of new treatments for bacterial pneumonia that modulate the activity of specific mast cells proteins in ways that improve survival.
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