# A20 Mediated Regulation of Colitis and Spondyloarthritis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $362,625

## Abstract

Project Summary/Abstract
Recent biologic and genetic studies implicate ubiquitination in the regulation of several inflammatory and cell
survival pathways in inflammatory bowel diseases (IBD). IBD is manifested by mucosal ulceration, loss of the
integrity of the intestinal epithelium, and inflammation of the gut mucosa. The events that lead to disruption of
the intestinal barrier in IBD are incompletely understood. We have been studying a potent regulator of
ubiquitin dependent signaling that is linked genetically and epigenetically to IBD, called A20 (also known as
TNFAIP3). A20 is a negative regulator of NFκB that limits inflammation and restricts multiple cell death
pathways. As death of intestinal epithelial cells (IECs) could compromise the intestinal barrier and contribute
to IBD, in this proposal we focus on A20's role in preserving IEC survival to protect against IBD. During our
investigations of A20, we observed that the expression of another ubiquitin-mediator, called ABIN-1, was
increased in cells when A20 was deleted. ABIN-1 (also known as Tnip1) is also genetically linked to IBD and
binds to A20. While A20 is a ubiquitin (Ub) editing enzyme, ABIN-1 binds poly-Ub chains. The functional
relationship between A20 and ABIN-1 has never been studied in vivo. Our recent studies have unveiled a
surprising and dramatic epistatic relationship between A20 and ABIN-1. These observations have led us to
hypothesize that A20 and ABIN-1 protect against IBD by preserving survival of IECs, in addition to their ability
to restrict immune cell activation. Accordingly, we propose to explore how A20 and ABIN-1 work together to
maintain intestinal barrier function and homeostasis in a new mouse model in which A20 and ABIN-1 are
inducibly and specifically deleted in intestinal epithelial cells. We will test how these proteins regulate cell
autonomous survival pathways in intestinal organoid cultures. To understand the precise mechanisms by
which A20 and ABIN-1 function, we have created several knock-in lines of mice with strategic point mutations
that abrogate specific biochemical functions of A20 and ABIN-1. Using these new mouse strains, we will
determine the biochemical functions of A20 and ABIN-1 that support IEC survival. The proposed studies will
establish a new, inducible mouse model of IBD that will allow dissection of the physiological preservation of
IEC homeostasis. The delineation of the ubiquitin controlled molecular pathways that lead to IEC death will
yield mechanistic insights into how to intercede in the disease course to promote intestinal healing.

## Key facts

- **NIH application ID:** 9881264
- **Project number:** 5R01DK095693-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** AVERIL I MA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,625
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881264

## Citation

> US National Institutes of Health, RePORTER application 9881264, A20 Mediated Regulation of Colitis and Spondyloarthritis (5R01DK095693-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881264. Licensed CC0.

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