PROJECT 1 - Host Neuraminidases in Hemostasis and Sepsis

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SUMMARY Coagulopathy and inflammation are the primary contributors to organ failure and patient death in sepsis. Among the top five causes of human mortality worldwide, the number of sepsis cases diagnosed annually now exceeds that of cancer. Among survivors, many suffer lifelong debilitation with cognitive decline from the extensive vascular damage of the host response. Decades of failure in the development of effective therapeutics for sepsis are reflected by the continuing high rate of patient mortality while many billions of dollars of healthcare costs are expended annually. It has become evident that a greater mechanistic understanding is needed regarding the molecular pathophysiology of this deadly syndrome. This project addresses this need with proposed research of a recently discovered mechanism of glycoprotein remodeling, senescence, and clearance that participates in disparate pathways modulating the coagulopathy and inflammation in sepsis. We have linked the step-wise post-translational remodeling of nascent blood glycoproteins by multiple glycosidases to increased protein age in circulation and to the formation of ligands for endocytic lectin receptors. This process normally determines the half-lives and functions of multiple blood components. Rates of this remodeling are altered in sepsis and among different blood components often linked to pathogen identity. Increased rates of remodeling rapidly change the abundance and functions of key glycoproteins including anti-inflammatory enzymes, coagulation factors, and platelets. Our findings are consistent with the hypothesis that sepsis is not a singular disease mechanism and may be further understood and stratified by analyzing alterations in host glycoprotein remodeling in the context of discrete pathogen identities and associated toxins. This may have important implications for designing future therapeutic approaches. The aims of this project encompass this perspective and the central hypothesis of the program: Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Research proposed herein includes the identification and characterization of glycosidases and lectin receptors in the blood and vascular systems contributing to blood component modulation and mechanisms of coagulopathy and inflammation in sepsis. Blood glycoproteins desialylated by host Neu1 and Neu3 neuraminidases will be identified and characterized including those targeted for increased endocytic clearance in sepsis. The related process of platelet aging and clearance and its increase in sepsis will be further investigated. Recent findings demonstrate a mysterious collaborative interaction between the Ashwell-Morell receptor of hepatocytes and the macrophage galactose lectin of Kupffer cells. This project will also continue to acquire and analyze medical records and blood samples provided by human sepsis patients and volunteers to achieve further translational links yielding mechanistic, prognostic, and therapeutic insights. These enzymes and receptors together contribute to distinct and overlapping molecular pathways in the stratification and pathogenesis of sepsis.