# Project 1: Glycosidases in the Coagulopathy and Inflammation of Sepsis

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $533,681

## Abstract

SUMMARY
The coagulopathy and inflammation of sepsis remain medical problems that are among the top five causes of
human death. Those surviving severe sepsis and septic shock may further suffer lifelong debilitation with
cognitive decline from the extensive vascular and organ damage of the host response. Decades of failure in
the development of effective therapeutics for sepsis are reflected by the continuing high rate of mortality and
the billions of dollars of healthcare costs expended on sepsis patient treatment each year. It has become
evident that a greater understanding is needed of host factors that modulate the pathophysiology of this deadly
syndrome. This project proposal is based on the recent discovery of a mechanism of glycoprotein senescence
and turnover that operates in normal physiology to control the half-lives and abundance of multiple
glycoproteins in the blood. Protein glycosylation creates multiple types of glycosidic linkages, including
asparagine-linked N-glycans that are prevalent on blood glycoproteins. Preliminary data has revealed that N-
glycans of blood glycoproteins are normally remodeled at a basal rate by circulating glycosidases during
glycoprotein aging, resulting in the appearance of ligands for multiple endocytic lectin receptors. This host
mechanism of glycoprotein senescence and turnover is altered in sepsis and has been demonstrated to affect
disease outcome. Proposed studies include a focus on multiple specific glycosidases including mammalian
neuraminidases, β-galactosidases, and β-N-acetylglucosaminidases that contribute to this innate mechanism
of glycoprotein remodeling that regulates glycoprotein homeostasis and function. The research proposed
includes corresponding lectin deficiency states to identify receptor-ligand relationships that alter pathogenesis.
This project will utilize all of the core facilities proposed in this program while addressing the central hypothesis
that protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis.
These studies will incorporate multiple bacterial pathogens spanning Gram-positive and Gram-negative
organisms, and the findings will be compared to a model of the non-microbial Systemic Inflammatory
Response Syndrome (SIRS). Mouse sepsis models as well as human sepsis patients with sepsis or SIRS will
be studied for alterations in blood glycosidase expression and blood proteomes to link mechanisms of
glycoprotein homeostasis and lectin receptor function with disease outcome. Preliminary data have identified
multiple blood components regulated by this novel mechanism of glycoprotein senescence and turnover, and
have established different disease pathways and molecular targets for therapeutic intervention. Findings
further indicate that the pathogenesis of sepsis is not a singular disease process but is determined in part by
the identities of bacterial pathogens involved. This has important implications in designing future therape...

## Key facts

- **NIH application ID:** 9916813
- **Project number:** 5P01HL131474-05
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** JAMEY MARTH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $533,681
- **Award type:** 5
- **Project period:** — → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916813

## Citation

> US National Institutes of Health, RePORTER application 9916813, Project 1: Glycosidases in the Coagulopathy and Inflammation of Sepsis (5P01HL131474-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9916813. Licensed CC0.

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