# Glycosyltransferase Function in Development and Disease

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $487,500

## Abstract

Summary
The pathogenesis of tissue-specific autoimmune disease reflects innate or acquired defects in immunological
tolerance but remains poorly understood. In Type 1 diabetes (T1D), a cell type-specific defect in immunological
tolerance results in the destruction of pancreatic beta cells. Although dysregulation of the immune system
represents a pathogenic component of this disease, the reason why pancreatic beta cells are targeted is not
understood. Discovering the bases of tissue-specific autoimmunity will enhance our understanding of the
mechanisms of immunological tolerance and will aid in the development of preventative and curative
approaches to autoimmune diseases such as T1D. This research proposal is focused on a hypothesis
supported by significant preliminary data that the susceptibility of pancreatic beta cells to immunological attack
in autoimmune diabetes reflects low levels of toleragenic sialic acids. In the past decade, novel studies have
linked the post-translational modification of proteins by sialyltransferases with immunological regulation.
Sialyltransferases are conserved and highly regulated enzymes that generate sialic acid linkages on the distal
ends of glycan chains. Sialic acid linkages can form ligands of various receptors including the Siglec receptors
of immune cells. Siglecs bind sialic acids in cis and trans at cell surfaces and thereby control the co-localization
and signaling of immune cell receptors. For example, Siglec binding to cell surface sialic acid linkages induces
immunological tolerance and inhibits the onset of autoimmunity in various mouse models at least in part by
blocking autoantibody production coincident with induction of B lymphocyte anergy and apoptosis. Most
mammalian cell surfaces are covered with toleragenic sialic acid linkages. However we have unexpectedly
observed low levels of sialic acid linkages present on the surface of normal pancreatic beta cells. This intrinsic
low level of sialic acids appears advantageous in normal physiological contexts requiring glucose uptake and
sensing, but appears disadvantageous in the presence of a dysfunctional immune system. To identify the
mechanistic features of immunological tolerance to pancreatic beta cells, we have initially studied the Non-
Obese Diabetic ShiLT/J (NOD) mouse because of its well-defined disease signs that include spontaneous
insulitis progressing to beta cell destruction, and because of the large body of immunological knowledge that
has been achieved using this model of human T1D. We have generated and analyzed transgenic and
syngeneic NOD mice bearing increased expression of sialic acids on pancreatic beta cell glycoproteins.
Remarkably, our findings reveal that augmentation of sialic acid linkages protects NOD mice from insulitis and
the immunological destruction of pancreatic beta cells. The research proposed herein will investigate sialic acid
linkage expression in normal human and mouse tissues, compare results of augmented ex...

## Key facts

- **NIH application ID:** 9901503
- **Project number:** 5R01DK048247-23
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** JAMEY MARTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 1994-09-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901503

## Citation

> US National Institutes of Health, RePORTER application 9901503, Glycosyltransferase Function in Development and Disease (5R01DK048247-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901503. Licensed CC0.

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