# A stress inducible Pdx1 transcriptional complex governing beta cell survival

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $451,633

## Abstract

Project Summary
Failure of pancreatic β cells underlies the progression of all forms of diabetes. β cells are uniquely
susceptible to stress induced cell death due to the high demand of insulin biosynthesis and
secretion and to oxidative stresses resulting from well-documented low antioxidant enzyme
activity. Pancreatic and duodenal homeobox 1 (PDX1) is a human diabetes gene and transcription
factor that is required for β cell function and survival during islet compensation for diet induced
insulin resistance. We find Pdx1 in complex with Activating Transcription Factors (ATFs) which
are well known to coordinate cellular stress responses. We hypothesize that PDX1, ATF4, and
ATF5 form a stress responsive transcriptional regulatory complex that directs β cell fate under
stress conditions. This will be tested in three Specific Aims: 1. Characterize the stress-induced
PDX1 transcriptional complex, 2. Identify the transcriptional targets of the stress-induced PDX1
transcriptional complex, and 3. Elucidate the functional roles of PDX1 targets in β cell survival.
We will employ cutting edge proteomic techniques to identify the components of the stress-
induced PDX1 transcriptional complex and any associated post-translational modifications.
Further, we will integrate ChIPExo and RNASeq profiles of mouse and human β cells under
physiologically and pathophysiologically relevant stress to obtain a comprehensive genome wide
identification of the transcriptional targets of this complex, leveraging the near base pair resolution
of ChIP-Exo to resolve structurally distinct modes of transcription factor binding, thereby enabling
new insights into stress responsive gene regulation in the beta cell. Finally, we will pursue the
functional role of the Pdx1-Atf4-Atf5 target Gpt2 in primary mouse and human islets to test the
hypothesis that the beta cell is metabolically reprogrammed by fuel excess in a manner analogous
to what occurs during transformation of cancer cells. Together these results will describe new
gene targets that regulate the cell fate decisions important for β cell survival in response to
diabetes related stresses, and expand the translational applications for human diabetes of the
PDX1 stress responsive transcriptional complex.

## Key facts

- **NIH application ID:** 9869011
- **Project number:** 5R01DK121175-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DORIS A STOFFERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,633
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869011

## Citation

> US National Institutes of Health, RePORTER application 9869011, A stress inducible Pdx1 transcriptional complex governing beta cell survival (5R01DK121175-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9869011. Licensed CC0.

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