Critical illnesses such as sepsis and acute respiratory distress syndrome are characterized by increased local and often systemic expression of pro-inflammatory cytokines. These mediators are expressed in response to activation of cellular components of the immune system, especially monocytes and macrophages, by a myriad of external stimuli. The manner by which signals are transmitted from the cell surface to the nuclei to initiate gene transcription proceeds through complex signal transduction pathways mediated by kinase-mediated, reversible phosphorylation of proteins. This process is balanced in part by a de-phophorylating system of phosphatases which may provide an endogenous regulatory system for modulating kinase activity. A key kinase pathway relevant to the gene expression pattern observed in critical illness is the N-terminal jun kinase (JN) that regulates transcription via the activating protein (AP)-I transcription complex. Preliminary data suggests that this kinase activity is regulated by the serine/threonine phosphatase, PP2A. Additional data suggest that physical associations exist between PP2A and multiple members of the JNK pathway. However, the precise molecular target(s) of this mechanism have not been identified, nor has the nature of the protein- protein interactions been characterized.
Specific Aim I is designed to determine the molecular targets of PP2A regulation of endotoxin-induced JNK MAPK pathway signaling in monocytes.
Specific Aim II is designed to define the protein-protein interactions between PP2A sub-units and members of the JNK MAPK pathway and to determine the nature of the key structural components facilitating these interactions.
Specific Aim III is designed to define the in vivo role of PP2A in immune active cells in modulating the JNK MAPK response to an inflammatory challenge using transgenic methodology. These results should provide novel insight into key functional and structural regulatory mechanisms and inform model development for phosphatase regulation of inflammatory-triggered kinase activity. Ultimately, it is hoped that this mechanistic understanding at the molecular level can be translated to provide better insight at the physiologic level so that more rational therapeutic strategies can be developed that are aimed at improving the survival of patients with critical illness.
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