Severe sepsis has a significant impact on public health with an estimated incidence of nearly 800,000 cases per year, resulting in over 200,000 deaths and an annual cost of over $17 billion. The pathophysiology of sepsis involves a dysregulation of the inflammatory response leading to an imbalance between pro-inflammatory and anti-inflammatory mediators resulting from the complex interactions of signal transduction pathways. A more comprehensive understanding of the regulation of the signal transduction pathways involved is necessary to identify novel therapeutic targets. The Mitogen Activated Protein Kinase pathway (MAPK), a primary signal transduction pathway involved in sepsis, is comprised of cascades of kinases that when activated ultimately lead to the production of inflammatory cytokines. The dual-specific phosphatases are a family of enzymes that dephosphylorate and deactivate the kinases of the MAPK pathway. The prototypical dual-specific phosphatase, MAP kinase phosphatase-1 (MKP-1), has been shown to be a negative regulator of the pro- inflammatory response. However, the regulatory role of MKP-2, a phosphatase closely related to MKP-1, in sepsis has not been studied. Our preliminary data show improved survival and decreased pro-inflammatory cytokine expression following intraperitoneal injection of lipopolysaccharide (LPS) in mice lacking MKP-2 expression. The objectives of this proposal are first to elucidate the role of MKP-2 in modulating pro-inflammatory gene expression and organ injury triggered by experimental sepsis and second to provide a mentored environment for the PI to establish a foundation upon which to build an independent research career as a Physician-Scientist. The central hypothesis is that MKP-2 is induced and positively regulates pro-inflammatory pathways activated during the course of sepsis.
The specific aims of this proposal are I) to investigate the regulatory control of MKP-2 induction following Toll-Like Receptor (TLR) stimulation, II) to study the regulatory effects of MKP-2 on the ERK, JNK and p38 MAPK pathways involved in sepsis-induced cytokine/chemokine gene expression and III) to determine the effects of MKP-2 deletion on cytokine expression, organ injury and pathogen clearance using established models of sepsis.
These aims will be investigated by the PI under the mentorship of Dr. Steven Kunkel and co-mentorship of Dr. Thomas Shanley in the Immunology program at the University of Michigan.
The relevance of this project to public health is that these studies are likely to provide important and novel insight as to the role of MKP-2 in the regulation of signal transduction pathways involved sepsis. Such an understanding will aid in the development of novel therapeutic strategies for patients with sepsis reducing the morbidity and mortality associated with the disease. This project will also provide career development for a Pediatric Intensivist increasing the critically low number of Physician- Scientists in the area of Pediatric Critical Medicine.
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