# Improving intestinal symptoms in a Congenital Disorder of Glycosylation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $601,661

## Abstract

PROJECT SUMMARY/ ABSTRACT
Congenital disorders of glycosylation are multi-system inherited diseases, which affect the amount of
glycosylation added to proteins. For patients with mannose phosphate isomerase (MPI) deficiency, decreased
mannose production leads to globally decreased levels of N-linked glycans resulting in several issues with
congenital diarrhea and protein losing enteropathy being the most significant symptoms. Our long-term
objective is to determine how defective glycosylation manifests as disease. We aim to achieve this objective
using a novel mouse strain named benadryl, which has an Mpi mutation and models most of the features of
human disease. We found conditional knockout of Mpi in the intestines re-created cardinal features of the
benadryl strain with severe defects in the mucus producing goblet cells, and features of inflammatory bowel
disease. The goal of this project is to determine how Mpi protects the intestines and how to improve therapeutic
interventions for patients deficient in Mpi. The central hypothesis is that Mpi is a rate limiting step for N-
glycosylation of mucins like Muc2, which are essential for proper mucin maturation and barrier function. In this
proposal we will investigate (Aim 1) how N-glycosylation of Muc2 is required for goblet cell survival, intestinal
mucus production, and protection from bacteria; (Aim 2) how N-glycosylation sites are essential for proper Muc2
folding and dimerization; and (Aim 3) the mechanism for how mannose therapy protects gastrointestinal barriers.
Upon finishing these studies, we will have defined the role of N-glycosylation post-translation modification of
Muc2 in maintaining a proper intestinal mucus barrier to prevent bacterial invasion and inflammation. Further,
we will leverage N-glycosylation insights to test feasibility and mechanism of mannose as a therapy in pre-clinical
models of gastrointestinal disease.

## Key facts

- **NIH application ID:** 10881362
- **Project number:** 1R01DK135511-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jeffrey SoRelle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,661
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881362

## Citation

> US National Institutes of Health, RePORTER application 10881362, Improving intestinal symptoms in a Congenital Disorder of Glycosylation (1R01DK135511-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881362. Licensed CC0.

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