# Regulatory Mechanisms of Glycoprotein Sialylation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $509,233

## Abstract

Summary
A major gap in the “bench to bedside” paradigm is the ability to harness the glycome for the development of
novel therapeutics. Although decades of research in glycobiology have established glycomic changes associated
with disease, almost nothing is known about how those changes arise, the functions they play in disease initiation
or progression, or how the glycome is actually regulated. Based on provocative new data, we propose a
transformative new model for glycomic compositional regulation of soluble secreted glycoproteins that provides
a clear path for the development of the first generation of glycan-modulating therapies for a wide range of
diseases. The model is based on the notion that the glycans of glycoproteins can be remodeled after release
from the originating cell, and if correct, our findings will refute the glycobiology dogma in which glycomic changes
are dependent upon the slow process of protein turnover and de novo synthesis to one that is highly dynamic,
rapid, and specific to the immunologic environment. The proposal centers on the molecular action, regulation
and necessary microenvironment for ST6Gal1 to add α2,6-linked sialic acids onto glycans with available terminal
galactose residues. Our proposal also focuses upon the B cell-secreted glycoprotein/antibody IgG. This is a
critical pathway to understand because ST6Gal1 is the sole enzyme that determines whether anti-inflammatory
α2,6-sialyl-IgG or pro-inflammatory asialyl-IgG is produced at any given time, thereby making it a key
immunomodulatory factor. In Aim 1, we will dissect the enzymatic action of ST6Gal1 from hematopoietic cells
other than B cells during IgG production. In Aim 2, we will extend our studies to the microenvironment necessary
to support ST6Gal1 activity in modifying IgG sialylation. Even if our model for glycoprotein glycan remodeling is
limited to sialylation, such a pathway could influence immune pathways such as leukocyte trafficking, the
distinction between self and non-self by siglecs, synthesis of the ABO blood groups, transplantation, IgG
functionality and many others. Our findings could redefine the nature of the glycome as one under dynamic
regulation that could be therapeutically harnessed via the creation of an entirely new class of glycosylation-
altering drugs for the treatment of diseases ranging from inflammatory disorders and autoimmunity to cancer.

## Key facts

- **NIH application ID:** 10152265
- **Project number:** 2R01GM115234-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Brian A Cobb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,233
- **Award type:** 2
- **Project period:** 2016-09-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152265

## Citation

> US National Institutes of Health, RePORTER application 10152265, Regulatory Mechanisms of Glycoprotein Sialylation (2R01GM115234-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152265. Licensed CC0.

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