The molecular and cellular processes that maintain a physiological balance in blood coagulation and inflammation are acutely altered in sepsis. The resulting coagulopathy and inflammation cause disability and death among a large proportion of sepsis patients throughout the developed and undeveloped world. Millions of patients are diagnosed with sepsis each year, with the associated expenditure of tens of billions of dollars in health care costs. Still, sepsis is increasing in incidence with the prevalence and virulence of infectious pathogens. Lack of sufficient knowledge of the pathophysiology of sepsis including host responses has primarily contributed to the paucity of current treatments. This program project integrates the expertise of multiple biomedical scientists and clinicians whom have recently made potentially transformative and translational discoveries of host responses in sepsis that remodel glycoproteins of the blood and vasculature. This remodeling alters glycan linkages on blood glycoproteins and diminishes heparin sulfate proteoglycan tethering to the vascular wall, resulting in changes to the half-lives, abundance, and functions of blood and vascular glycoproteins with a profound impact on the coagulopathy, inflammation, and lethality of sepsis. Further discoveries that this program project team are poised to make are expected to achieve significant advances in the mechanistic understanding of the life-threatening changes to host blood and vascular systems during sepsis. The program is integrated by a central hypothesis proposing that Protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. The research projects are highly synergistic with interdisciplinary and state of the art technologies that span four core facilities to support three research projects that all address the central hypothesis of the program. The overall objective is to identify and investigate blood and vascular glycoprotein remodeling mechanisms and their multiple effects on coagulopathy, inflammation, and the outcomes of Gram-negative and Gram-positive bacterial sepsis in mice and compared with the underlying Systemic Inflammatory Response Syndrome (SIRS). The program will also incorporate analyses of blood samples from human patients diagnosed with sepsis or SIRS.
The research aims encompass investigations of coagulation, tissue coagulopathy, inflammation markers, glycan linkages, serology, pathogen burden, and comparative proteomic analyses of blood samples. Recent findings demonstrate that conserved glycoprotein homeostatic mechanisms differentially modulate the pathogenesis and outcomes of sepsis caused by distinct pathogens, supporting the emerging view that sepsis is not a singular disease process.
The specific aims of this program project are further derived from extensive preliminary data that supports the proposed studies. The combined results of this program will generate insights into host responses and mechanisms that modulate the coagulopathy and inflammation of sepsis, and will generate important information needed to develop more effective diagnostic and therapeutic approaches.
The coagulopathy and inflammation of sepsis are a major cause of human disability and death with millions of people affected in the U.S. each year. Death as an outcome still averages 30%, underscoring the incomplete knowledge 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 molecular mechanisms operating in the host that modulate the coagulopathy and inflammation of this deadly syndrome in order to transform the understanding and improve the treatment of sepsis.
