# Heavy metals exposure regulates secretory lineage in intestinal injury

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $379,123

## Abstract

PROJECT SUMMARY
Over 160,000 abandoned mine waste sites are concentrated in the western United States and continue to
degrade the environment with elevated heavy metals penetrating the surrounding sediment and groundwater.
The sedimentary dust and water used by communities located near abandoned uranium mine (AUM) sites
often exceeds the maximum contamination level for uranium (U, EPA max level 30 μg/L). Chronic exposure to
environmental toxins and heavy metals has been linked to intestinal inflammation, increased susceptibility to
pathogen-induced diseases, and higher incidences of colorectal cancer; all of which have been steadily
increasing in prevalence for the past 40 years. The negative effects of heavy metals on the intestinal
microbiota, barrier permeability, and inhibition of intestinal epithelial healing have been described; however,
transcriptomic changes within the intestinal epithelial cells are largely unknown. Upon ingestion, uranium is
poorly absorbed systemically (~1.5%) and thus distributed through the entire intestine, suggesting even low U
levels are sufficient to cause intestinal damage. Thus, our goals are to characterize particulate dust (referred to
as U-bearing dust, UBD) as an environmental toxicant that damages the intestinal epithelia and determine the
molecular changes that develop as a response to this injury. We have previously characterized the intestinal
mucus layer in human intestinal organoids (HIOs) under homeostasis and pathogen infected conditions, to
characterize HIOs as an intestinal pathophysiological model. Our preliminary data of HIOs exposed to UBD
found that chemical exposure negatively impacts the secretory lineage in the colon, specifically the mucus-
producing goblet cells and hormone-producing enteroendocrine cells. Thus, we hypothesize that UBD has a
direct effect on: 1) the mucosal surface, represented by a thinning mucus layer and goblet cell dysfunction
and 2) the intestinal enteroendocrine cells in the crypt. This leads to increased susceptibility to intestinal
disorders. The following Aims will address these questions in a mechanistic manner. The first aim will
determine the impact of UBD on mucus layer thinning, resulting pro-inflammatory response, and subsequent
goblet cell expansion. The second aim will examine the autophagy pathway in regulating changes in
enteroendocrine hormone secretion and the transcription factor PROX1 as the non-canonical driver of
enteroendocrine cell expansion following UBD chemical injury. There is a need to understand how heavy
metals, especially those naturally occurring as particulates, induce molecular changes in the intestinal epithelia
of exposed individuals to predispose them to intestinal disorders. Successful completion of this proposal will
help us understand the mechanistic underpinnings of environmental-induced injury that may promote colitis or
related diseases, identify potential therapeutic targets, and identify genetic variations that may contribu...

## Key facts

- **NIH application ID:** 10804040
- **Project number:** 1R01ES034400-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Julie Goeun In
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,123
- **Award type:** 1
- **Project period:** 2024-09-19 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804040

## Citation

> US National Institutes of Health, RePORTER application 10804040, Heavy metals exposure regulates secretory lineage in intestinal injury (1R01ES034400-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10804040. Licensed CC0.

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