# Determining the role of the creatine pathway regulation of intestinal goblet cell development in colitis

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2024 · $164,645

## Abstract

Proposal Summary
 Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, contributes to
significant morbidity and mortality in the United States. The inflammation in IBD is initiated by a breakdown in
the mucous layer and intestinal epithelial cells that act as a barrier in the gastrointestinal tract. Current
therapeutics are inadequate in that they largely target systemic immunosuppression which have been
associated with increased infection and malignancy risk as well as being efficacious in a minority of patients.
These problems result in many IBD patients having active and debilitating disease. We have previously
identified a key role for creatine, an energetic regulator, in intestinal epithelial cell barrier function and wound
healing. This is significant in that IBD patients have decreased expression of the creatine transporter (CRT)
which brings creatine into cells. More recently we have identified dysregulation of intestinal epithelial cell
differentiation in cells that are deficient for CRT. Loss of creatine results in decreased goblet cell marker
expression in CRT deficient organoids and decreased mucous containing goblet cells in the colon of
CrtFloxVillinCre mice. This deficiency decreases mucous layer formation, which is expected as goblet cells are
the major producers of the protective mucous layer which serves to protect the intestinal mucosa. In the follow
proposal we aim to evaluate the hypothesis that the creatine pathway is integral to goblet cell function and
dysregulation identified in CRT deficient epithelial cells will impact the microbiome and metabolism of the
colonic lumen as well as contribute to increased colitis susceptibility.
 In Specific Aim 1, we propose to evaluate the contribution of glycolysis on goblet cell differentiation and
activity in CRT deficient intestinal epithelial cells. We will also determine the cause of the dysregulation by
evaluating key goblet cell signaling pathways. This aim is vital in that identifying the mechanism of goblet cell
loss may provide options for therapeutic intervention. In Specific Aim 2 we will identify changes in microbiome
that could be impacted by the decrease in mucous and other goblet cell produced factors as well as changes
to the creatine content in the lumen. We will determine if these changes may contribute to a stressed
metabolic colonic lumen environment. We believe that alteration to the microbiome may contribute to the
inflammatory mucosal environment. Specific Aim 3 will assess for colitis disease susceptibility due to epithelial
CRT loss in CrtFloxVillinCre mice. We will conduct salmonella colitis and TNBS colitis experiments which cause
ulcerative colitis like inflammation in CrtFloxVillinCre mice and compare disease susceptibility. We will make use
of findings in the prior aims to determine if there are interventions to prevent increased susceptibility in
CrtFloxVillinCre mice including stimulation of differentiation pathways and...

## Key facts

- **NIH application ID:** 10863715
- **Project number:** 1K08DK139375-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** CAROLINE H HALL
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $164,645
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863715

## Citation

> US National Institutes of Health, RePORTER application 10863715, Determining the role of the creatine pathway regulation of intestinal goblet cell development in colitis (1K08DK139375-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863715. Licensed CC0.

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