# Modulation of NOD Strain Diabetes by ENU-Induced Mutations

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $2,198,935

## Abstract

PROJECT SUMMARY/ABSTRACT
This P01 proposal offers a fresh approach to understanding the genetics of an extremely important polygenic
autoimmune disease: type 1 diabetes (T1D), which affects nearly three children out of every thousand in North
America, and many more around the world. T1D occurs with variable penetrance in Non-Obese Diabetic (NOD)
mice, which exhibit a phenotype remarkably similar to that of human patients. Both environmental and genetic
factors determine penetrance, but most of the influential mutations and the genes they affect remain unknown.
We have developed a powerful technology platform that permits instantaneous identification of point mutations
that cause phenotype. Using this platform, we have already identified two spontaneous mutations that cause
high and low frequency of disease development in the NOD/NckH and NOD/NckL sublines, respectively. Noting
that these sublines, isolated by selective breeding over a period of only seven years, had approximately the
same mutational distance from one another as one finds in a pedigree of ENU mutagenized mice as compared
to the parental reference strain, we performed a pilot study in which mice were mutagenized on the NOD/NckH
background. In a sample of 14 pedigrees, we unambiguously identified twelve ENU-induced mutations with
modifying effects on T1D: some accelerating the disease and others suppressing it. Stressing the precision of
these studies, which do not merely identify intervals or candidates, but resolve the exact nucleotide change
responsible for T1D modification, we propose to expand our efforts, analyzing 21,000 coding/splicing mutations
for modifier effects over a period of five years. Our preliminary work suggests that T1D is “balanced on a knife’s
edge” from a genetic point of view. Mutations in many genes are clearly capable of influencing T1D development,
since randomly induced coding/splicing mutations affecting approximately 1% of the mouse genome caused
unambiguous modifier phenotypes. We expect to identify scores if not hundreds of individual modifier mutations
during the period of funding. Some of these will have important new facts to tell us about what it takes to develop
T1D. Concentrating on those modifier mutations that show large effect sizes, may be amenable to targeting with
therapeutic drugs, and/or are particularly surprising in light of what we presently know about T1D pathogenesis,
we will rigorously verify causation by re-creating the mutations and/or deleting the causative genes on clean
backgrounds (NOD/NckH or NOD/NckL devoid of ENU-induced mutations). We will then systematically examine
the mechanism of phenotype modification, both at the level of cellular immuno-pathogenesis, and at the level of
molecular pathogenesis. Ultimately, we hope to understand how T1D can be prevented or driven into remission,
and we expect many new insights to emerge from the studies planned. A close collaboration between the
Bach/Chatenoud group, with its great ...

## Key facts

- **NIH application ID:** 10866448
- **Project number:** 5P01AI165026-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** BRUCE A BEUTLER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,198,935
- **Award type:** 5
- **Project period:** 2023-06-13 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866448

## Citation

> US National Institutes of Health, RePORTER application 10866448, Modulation of NOD Strain Diabetes by ENU-Induced Mutations (5P01AI165026-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866448. Licensed CC0.

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