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

Award Number: F31DK148130
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Investigating the roles and dynamics of the endoplasmic reticulum during paligenosis and metaplasia formation - 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. The upstream triggers and molecular mechanisms initiating this regenerative program remain poorly understood. 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 elF2a. Phosphorylated elF2a 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 lime 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 Pefkllll 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. Using ER-phagy defective mice (Ccpgt+), the effect of ER-phagy deficiency on paligenosis will be examined. The necessity of ER-phagy receptor in initiating and regulating autophagy will also be examined in a clinically relevant context, using human gastric adenocarcinoma cell line AGS and patient-derived organoid models of normal gastric corpus and intestinal metaplasia. This fellowship project ultimately seeks to define critical upstream events that initiate cellular reprogramming during regeneration, providing new insights into ER stress signaling and ER-phagy in gastrointestinal tissue repair and disease. This fellowship also supports a mentored training plan focused on the development of skills related to project management, imaging and analytical techniques, teaching, communication, leadership, and outreach.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/23/2026	NEW	$0
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/23/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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

Award Number: F31DK148130

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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