The aims of this project address the central hypothesis of the overall program, that Protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. This research project will investigate the roles of heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), and matrix metalloproteases (MMPs) in the coagulopathy and inflammation of sepsis. The proposed research engages all of the core facilities of the program and draws on the combined expertise of the Project Leaders and Core Leaders in infection and sepsis, inflammatory biology, coagulation, coagulopathy, proteomics, and glycobiology. From recent literature and preliminary data, HS attached to endothelial HSPGs alters the outcome of sepsis coincident with HSPG shedding from vascular endothelial cells induced by MMPs. Moreover, vascular HS deficiency has opposing effects on the outcomes of sepsis caused by different microbial pathogens including Gram-positive Streptococcus pneumoniae (SPN) and Gram-negative Salmonella enterica Typhimurium (ST). In addition, MMP inhibition affects HSPG shedding and provides a protective role in the pathogenesis of sepsis caused by ST. These findings infer the possibility that the pathogenesis of sepsis may be stratified by different host responses in the context of distinct pathogens. Research proposed in Project 3 will further test the hypothesis that the major HSPGs expressed on the vascular endothelium, namely syndecan-1, syndecan-2, syndecan-4, and glypican-1, compose a functional nexus with MMPs that confer separate outcomes in the coagulopathy and inflammation of sepsis caused by these bacterial pathogens and Gram-negative Escherichia coli (EC). This project will also generate unique knowledge about the repertoire of HSPG-protein complexes in disease onset and progression. The proposed studies will focus on HSPGs and HS-binding proteins in mice and humans during sepsis caused by Gram-negative and Gram-positive pathogens, and in Systemic Inflammatory Response Syndrome (SIRS) and may yield new potential biomarkers and novel approaches to modulating the outcomes of sepsis and SIRS. The interdisciplinary expertise of the Project Leaders and Core Leaders, and the combined resources available, will achieve a mechanistic understanding of HSPG homeostasis and HSPG-protein complex determinants implicated in modulating the coagulation, coagulopathy, inflammation, and outcomes of SIRS and sepsis due to infections involving different pathogens.
The coagulopathy and inflammation of sepsis are a major cause of human disability and death, with over a million people affected in the U.S. each year. Death as an outcome still averages 30%, underscoring the incomplete knowledge of the pathogenesis of sepsis and the need for breakthroughs in biomedical research of this long-standing problem. This research proposal will focus on newly discovered and previously understudied biological mechanisms operating in the host that modulate the coagulopathy and inflammation of this deadly syndrome in order to transform the understanding and treatment of sepsis.
