The major cause of delayed deaths following severe trauma is multiple organ dysfunction syndrome (MODS), including acute respiratory distress syndrome (ARDS). The underlying etiology of MODS is Ithought to be an excessive systemic inflammatory response syndrome (SIRS) causing disseminated tissue injury. The monocyte/macrophage (MPh) is a central coordinator of both the normal and aberrant host immuno-inflammatory response and is thought to be crucial for the induction and persistence of this """"""""malignant systemic inflammatory response."""""""" The MPh is either """"""""primed"""""""" or immunosuppressed, dependent upon the phase of injury recovery, and produces a dysfunctional innate immune response to the multiple stimuli in the inflammatory milieu. Previous therapeutic approaches have focused on inhibition of single mediators of the host response. However, since the inflammatory response is replete with redundance and feedback amplification loops, it is theoretically more appealing to broaden our focus to more globally control the inflammatory injury and, thus, improve patient outcome. Hypothesis: the aberrant dysfunctional Mo immuno-inflammatory response can be modulated by manipulation of the cellular signal transduction mechanisms that control the expression of multiple inflammatory mediator genes. Elucidation and control of these MPh cellular mechanisms will target the potential development of safe, therapeutic interventions to potentially prevent ARDS, MODS and death in these critically ill patients. The following specific aims will be pursued: 1) delineate selective activation patterns of intracellular signal transduction pathways (MAPK family) to varying stimuli and cell specificity; 2) investigate signal initiation processes (including TLR-4, IRAK and PYK-2) and the need for an intact cytoskeleton; 3) identify potential response regulators, including CaMK, PKA and PKC; 4) elucidate the endogenous counter-regulatory mechanisms, including kinase-specific phosphatases; and 5) correlate signal activation pathways with subsequent genomic and proteomic response profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045873-14
Application #
6749535
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1991-04-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
14
Fiscal Year
2004
Total Cost
$326,357
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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