# Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $522,380

## Abstract

Abstract
The endoplasmic reticulum (ER) is best known for its role as the locus of protein folding, calcium storage, and
lipid metabolism. The organelle also integrates numerous other molecular pathways and contributes to cellular
calcium homeostasis, reduction-oxidation regulation, and cell death. Given the many vital and complex functions
of the ER, it is little wonder that its failure can trigger a range of diseases. It has been shown that dysregulation
of ER homeostasis may underlie β cell dysfunction and death in type 1 and type 2 diabetes, as well as in
monogenic forms of diabetes, including Wolfram syndrome, Wolcott-Rallison syndrome, microcephaly, epilepsy,
and diabetes syndrome (MEDS), and mutant insulin gene-induced diabetes caused by pathogenic variants in
the WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes respectively. To further understand the contribution
of ER dysfunction to β cell death and design novel treatments targeting ER for diabetes, we need to establish
functional studies of gene variants affecting ER homeostasis, design treatments targeting common molecular
pathways altered in ER stressed β cells, and identify other ER genes involved in β cell dysfunction and death. In
this proposal, we will characterize WFS1 and CISD2, EIF2AK3, IER3IP1, and INS variants using functional
assays and bioinformatics and test novel treatments targeting the common molecular pathways altered in β cells
expressing pathogenic variants of WFS1 and CISD2, EIF2AK3, IER3IP1, and INS genes. Successful completion
of this study will lead to the establishment of precision medicine for hereditary ER diabetes.

## Key facts

- **NIH application ID:** 10830306
- **Project number:** 5R01DK132090-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bohdan Khomtchouk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $522,380
- **Award type:** 5
- **Project period:** 2022-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830306

## Citation

> US National Institutes of Health, RePORTER application 10830306, Molecular Genetics of Hereditary Endoplasmic Reticulum Diabetes (5R01DK132090-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10830306. Licensed CC0.

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