# microRNA-dependent regulation of intestinal T-cells²

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $349,875

## Abstract

Project Summary
Our intestines comprise over 50% of our bodies immune cells and tightly maintains a constant state of
homeostasis against foreign stimulus like food particles and bacteria. This immune “tolerance” is broken during
chronic intestinal inflammation as seen during inflammatory bowel diseases (IBD). Adverse CD4+ THelper
responses perpetuate the chronic pathology observed in IBD, thus understanding the molecular mechanisms
that control their function is central to endeavors of finding novel therapeutic treatments. A physiologic adaptive
response to inflammation is a marked shift in the supply and demand of metabolites that results in limited
oxygen availability (now termed inflammatory hypoxia) and activation of the transcription factors hypoxia-
inducible-factors (HIFs). While there are multiple affects of hypoxia on T cell gene function, the effects on post-
transcriptional regulation are underexplored. To investigate hypoxia-elicited tissue protective signaling we
performed a screen of CD4+ T cell-specific miRNAs and identified a selective induction of miR-29a. Studies
with genetic models identified a role of Hif-2α in miR-29a induction and subsequent experiments demonstrated
repression of the miR-29a target-genes Tbet and IFNγ (canonical TH1 markers) during hypoxia. Mice with a T-
cell-intrinsic deficiency in Hif-2α displayed elevated Tbet levels in CD4+ T cells and exacerbated inflammation
during experimental colitis. Based on these preliminary studies, we hypothesize that Hif-2α induction of miR-
29a suppresses TH1 CD4+ cell activation. In this proposal we will address this hypothesis with three integrated
lines of investigation. Firstly, we will examine how Hif-2α transcriptionally induces miR-29a and the functional
requirements for Hif-2α in CD4+ THelper differentiation. Second, we will assess the role of miR-29a in the
regulation of T cell mediated colitis. Lastly, in proof of concept studies we will target miR-29a stabilization in
vivo during experimental colitis. Collectively these studies aim to dissect the Hif-2α-miR-29a-Tbet axis in the
regulation of CD4+ T cell-mediated intestinal inflammation.!
!

## Key facts

- **NIH application ID:** 10090587
- **Project number:** 5R01DK111856-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Edwin Fulco de Zoeten
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,875
- **Award type:** 5
- **Project period:** 2018-01-13 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090587

## Citation

> US National Institutes of Health, RePORTER application 10090587, microRNA-dependent regulation of intestinal T-cells² (5R01DK111856-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10090587. Licensed CC0.

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