The overall goal of this project is to elucidate the role of the profibrinolytic annexin A2 (A2) system in the host response to sepsis, a disorder that causes more than 200,000 deaths annually in the U.S. This application is based upon the observations that, compared to A2+/+ mice, A2-/- mice have remarkably prolonged survival following intraperitoneal administration of lipopolysaccharide or the cecal ligation and puncture model of polymicrobial sepsis. In preliminary studies, we have found that while A2-/- mice have greater accumulations of microvascular fibrin during endotoxemia, they have unexpectedly reduced levels of tissue inflammation, despite extremely elevated levels of the pro-inflammatory cytokines interferon? (IFN?) and interleukin-1?. We have shown, moreover, that IFN? specifically enhances synthesis of the A2 binding protein, p11, thereby increasing translocation of the (A2?p11)2 complex to the cell surface. Based upon these preliminary data, we have developed four specific aims.
In Aim 1, we will determine whether resistance to endotoxemia and to polymicrobial sepsis in A2-/- mice reflects attenuated vascular fibrinolytic activity.
In Aim 2, we will define the role of IFN? and related cytokines in regulating endothelial cell surface A2 system-related fibrinolytic activity in vivo, and will define the roles of A2 and p11 in regulating inflammatory cell activation.
In Aim 3, we will delineate whether and how the A2 system affects lipopolysaccharide-toll-like receptor signaling, caspase-1-induced pyroptotic cell death, and inflammasome activation.
Aim 4 will focus on human sepsis syndromes with experiments designed to elucidate the expression level and activity of the A2 and p11 in human subjects with sepsis, and to determine whether plasma from sepsis patients regulates cellular A2 system activity and in a cytokine-dependent manner. Ultimately, we hope to elucidate the role of the endothelial cell annexin A2 system in the innate host response to sepsis, to determine whether the A2/p11 is a key modulator of the systemic response to sepsis, and to establish the theoretical groundwork that might support A2/p11- targeted therapies for this disorder.
Sepsis, or overwhelming bloodstream infection, occurs in some 750,000 people per year in the United States, and accounts for more than 200,000 deaths annually. There has been little progress in improving the fatality rate from sepsis over the past 10 years, and its incidence is rising due to our aging population and because of increasing survival of people with low immune system function. The overall goal of this application is to define how the annexin A2 system may determine outcomes in sepsis, thereby offering new targets for treatment of this disease.
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