# Genetic programming of human islet metabolic and endoplasmic reticulum (ER) stress responses in diabetes

> **NIH NIH R01** · JACKSON LABORATORY · 2022 · $784,967

## Abstract

PROJECT SUMMARY
Type 2 diabetes (T2D) results from failure of pancreatic islets to secrete sufficient insulin to compensate for
increased insulin resistance in peripheral tissues. Precise understanding of the molecular mechanisms
underlying genetic and environmental contributions to islet failure is essential to develop new, targeted
approaches to prevent and treat T2D. Endoplasmic reticulum (ER) and (gluco)lipotoxic stress responses are
central (patho)physiologic processes that contribute to islet dysfunction and failure. Our overall objective in this
proposal is to elucidate the genetic regulation of islet stress responses and to determine how genetic variants,
including SNPs associated with T2D and other metabolic traits (T2D SNPs), modulate these responses to
contribute to islet dysfunction and T2D pathogenesis. Based on previous studies and preliminary data, we
hypothesize that T2D SNPs alter human islet stress responses by changing islet regulatory element (RE)
use/function and expression of their target genes to contribute to islet dysfunction and T2D. In Aim 1, we will
test this hypothesis by characterizing islet ER and (gluco)lipotoxic stress responses at the level of gene
expression and identifying genetic variants altering human islet stress responses. For this, we will use bulk and
single-cell RNA-Seq as well as computational analyses to discover response expression quantitative trait loci
(reQTL). In Aim 2, we will take a complementary epigenomic approach to elucidate genetic effects on stress
response regulatory element (RE) use in human islets. From the same islets as in Aim 1, we will determine the
genome-wide location of REs at steady state and after exposure to stressors using the assay for transposase
accessible chromatin-sequencing (ATAC-seq). Using these data, we will computationally identify transcription
factors binding to these REs, identify genetic variants altering stress-responsive RE use by chromatin
accessibility quantitative trait locus (caQTL) analyses, and test allelic effects on stress-responsive RE activity
using massively parallel reporter assays (MPRA) in beta cell lines. Finally, we will experimentally manipulate
these islet stress-responsive genes in human EndoC-ßH3 beta cells using CRISPR/Cas9 (epi)genome editing
to determine their functions in beta cell proliferation, function, and survival (Aim 3). This study will provide
mechanistic insight into how human genetic variation modulates these T2D-relevant stress responses in
human islets. By delineating the genes and pathways that modulate islet (gluco)lipotoxic and ER stress
responses and experimentally validating their effects on islet/beta cell resilience, this study will reveal novel
therapeutic targets and guide strategies for subsequent studies manipulating these responses to prevent or
treat islet failure and T2D.

## Key facts

- **NIH application ID:** 10311552
- **Project number:** 5R01DK118011-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Michael Lee Stitzel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $784,967
- **Award type:** 5
- **Project period:** 2020-12-03 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311552

## Citation

> US National Institutes of Health, RePORTER application 10311552, Genetic programming of human islet metabolic and endoplasmic reticulum (ER) stress responses in diabetes (5R01DK118011-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10311552. Licensed CC0.

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