# Investigating the roles and dynamics of the endoplasmic reticulum during paligenosis and metaplasia formation

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Reprogramming is crucial for cellular renewal in adult organs that lack dedicated stem cells to replace loss after
injury and inflammation. Because such cell plasticity is likely to be executed by a conserved cellular program,
we have begun to identify the conserved cellular-molecular features of the process of recruiting differentiated
cells as progenitors. The term paligenosis has been recently coined to describe an evolutionary conserved
process that a differentiated cell uses to downscale its organelle contents, activate a progenitor-like gene
network, and reenter the cell cycle. This project investigates upstream triggers of paligenosis. Using a high-dose
tamoxifen injury model to induce paligenosis in zymogenic chief cells of murine stomach corpus, ultrastructural
changes in the rough endoplasmic reticulum (rER) were observed during paligenosis initiation (e.g., swelling of
the rER lamellae, liberation of ribosomes from rER, and overall loss of ER). This leads to the hypothesis that
dynamic changes in ER are an upstream event in paligenosis. ER functioning is in part monitored by the
integrated stress response with the paramount ER stress sensor being PERK, a kinase that inhibits translation
of mRNA on the ribosome by phosphorylating the translation initiation protein eIF2α. Phosphorylated eIF2α halts
global translation while upregulating a specific set of genes to restore homeostasis. Data show that high-dose
tamoxifen activates the integrated stress response in paligenotic zymogenic chief cells, triggering global
attenuation of protein synthesis. Preliminary data also indicate that disassembly of rER is an early paligenosis
event, supporting the hypothesis that early events of paligenosis are driven by the PERK-integrated stress
response pathway and the dynamic regulation and autophagy of rER. Aim 1 of this project thus seeks to detail
activation of PERK over a time course early in paligenosis in the high-dose tamoxifen injury model, and then test
the PERK requirement using PERK and integrated stress response inhibitors, and PerkΔ/Δ mice crossed to chief
cell-specific promoter mice. Sufficiency will be tested by inducing ER stress and by drug-induced activation of
PERK. Aim 2 will detail paligenotic ER remodeling in a high-dose tamoxifen model, as well as investigate the
impact of hydroxychloroquine treatment and blocking autophagolysome activity in paligenotic-lysosome-
defective Atf3−/− mice. Using ER-phagy defective mice (Ccpg1−/−), the effect of ER-phagy deficiency on
paligenosis will be examined. The project ultimately seeks to provide new insights on the dynamic functionality
of the ER and its role and necessity in homeostasis and during cellular regeneration.

## Key facts

- **NIH application ID:** 10999135
- **Project number:** 1F31DK141249-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thanh Nguyen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-08-27 → 2025-04-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999135

## Citation

> US National Institutes of Health, RePORTER application 10999135, Investigating the roles and dynamics of the endoplasmic reticulum during paligenosis and metaplasia formation (1F31DK141249-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10999135. Licensed CC0.

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