# Roles of circHIPK3 and HuR in aging gut barrier function

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $558,222

## Abstract

Abstract
 Despite the on-going debate as to whether there are changes in gut barrier function during healthy aging,
clinical studies consistently support an increased risk of infection, sepsis, and multiple organ dysfunction in
elderly patients following trauma and major surgical intervention. Among many contributing factors, impaired
barrier integrity of an aging gut is the essential factor to this increased risk. However, our current understanding
of the mechanisms underlying the increased vulnerability to gut barrier dysfunction during aging remains poor
and, as a result, effective therapies to preserve intestinal barrier integrity in old patients are limited. Maintaining
the gut epithelial barrier function is a complex process that requires epithelial cells to rapidly alter gene
expression patterns to regulate their interactions and survival, adaption to stress, and to maintain homeostasis.
Posttranscriptional events, particularly altered mRNA turnover and translation, are major mechanisms by which
mammalian cells control gene expression in response to various stresses. Regulation of mRNA stability and
translation is predominantly governed by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) including
circular RNAs (circRNAs). Recently, we have demonstrated that the RBP HuR regulates the epithelium host
defense in the intestine via Paneth cells and that the circRNA circHIPK3 enhances injury-induced regeneration
of the intestinal epithelium by reducing microRNA-29b function. However, the exact roles of HuR and circHIPK3
in regulating the intestinal barrier function in the aging epithelium remain unknown and how these new findings
can be exploited to benefit old patients is still unclear. Our preliminary results show that the level of circHIPK3
decreased remarkedly in the small intestinal mucosa of old mice and aged individuals, whereas aged mice with
HuR-deficiency exhibited an improved gut barrier function relative to age-matched control mice. Our preliminary
studies further revealed that HuR was potentially involved in promoting excessive mitochondrial clearance in the
old intestinal epithelium and that circHIPK3 acted as an enhancer of mitochondrial biogenesis. Based on our
exciting preliminary results and support from scientific literatures, we hypothesize circHIPK3 and HuR play
distinct roles in modulating mitochondrial function in aging intestinal epithelium, ultimately impacting gut barrier
function and vulnerability in the elderly undergoing pathological stress. Two specific aims are proposed to test
this hypothesis: 1) to test the hypothesis that circHIPK3 and HuR play key roles in the altered gut barrier function
observed in aging mice and humans under pathological stress compared to normal homeostasis; and 2) to test
the hypothesis that circHIPK3 and HuR regulate the epithelial barrier of the aged gut by altering IEC
mitochondrial metabolism. Completion of these specific aims will make a significant conceptual advance by
linki...

## Key facts

- **NIH application ID:** 10978312
- **Project number:** 1R01AG084613-01A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Lan Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $558,222
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978312

## Citation

> US National Institutes of Health, RePORTER application 10978312, Roles of circHIPK3 and HuR in aging gut barrier function (1R01AG084613-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10978312. Licensed CC0.

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