# The Role of Crypt Fissioning in IBD Ulcer Healing

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $691,717

## Abstract

Program Director/Principal Investigator (Barrett, Terrence, A):
The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data that
demonstrate it to be a predictor of remission1. Thus, ulcer healing predicts the capacity for therapies to prevent
unwanted clinical sequelae (i.e. surgery). Unfortunately, many IBD patients remain refractory or lose
responsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show that
reduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC)2. These findings
were supported by Kugathasan et al who found that increased expression of mitochondrial respiratory chain
genes predicted favorable (B1 protected) Crohn’s disease (CD) outcomes3. Based on these results and our
own data, we hypothesize that a critical driver of chronic ulceration in IBD is the failure of intestinal
epithelial cells (IEC) to increase mitochondrial respiration with ROS generation. We posit that chronic
mucosal inflammation suppresses mitochondrial respiration needed for crypt fissioning (in ulcer healing) in
IBD. This hypothesis will be tested in the following studies: Aim 1. Determine the impact of
mitochondrial respiration for mucosal healing. These studies benefit from strikingly novel Prelim.
Data using VilCre/mTmG/TFAMfl/fl mice where mitochondrial respiration was shown to be required for
crypt fissioning in ulcer healing. In Aim 2 we will determine the requirement of mitochondrial-
derived ROS in IEC crypt division using primary human colonoids. Aim 3 studies will determine
the impact of chronic inflammation on ulcer healing in patients. IEC transcriptomics from ulcer
edges from CD and ulcerative colitis will be compared to normal ulcer healing. Normal ulcer healing
will be interrogated using a novel biopsy of a biopsy (Bx/Bx) approach (IEC will be isolated from
Bx/Bx sites 4-6day after initial biopsies). ScRNAseq results have already shown that mitochondrial
biogenesis (PGC1) increases in Bx/Bx ulcers whereas levels drop in IBD IEC. In summary: Studies
will investigate the cause of non-healing ulceration in IBD by interrogating novel murine, human
and in vitro colonoid culture models of determining the impact of suppressed mitochondrial respiration
on IEC responses (crypt fissioning). The studies will test the notion that chronic mucosal
inflammation (as in IBD) suppresses mitochondrial respiration which impedes ROS-induced
PI3K signaling and crypt fissioning. Our goal is to identify therapeutic targets to allow for enhanced
mitochondrial respiration to aide mucosal repair in IBD.
OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10122313
- **Project number:** 2R01DK095662-10A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Terrence A. Barrett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $691,717
- **Award type:** 2
- **Project period:** 2021-02-24 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122313

## Citation

> US National Institutes of Health, RePORTER application 10122313, The Role of Crypt Fissioning in IBD Ulcer Healing (2R01DK095662-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10122313. Licensed CC0.

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