# MicroRNA-Suppressed Mitochondrial Fusion in Mediating the Teratogenicity of Maternal Diabetes Leading to Heart Defects

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $604,001

## Abstract

ABSTRACT
miRNAs, a class of small non-coding RNAs that silence gene expression, are critically involved in embryonic
cardiogenesis. We found that maternal diabetes up-regulated two miRNAs: miR-140 and miR-195, which
always work together in the pathology of adult cardiac diseases. This current project tests the hypothesis that
the upregulation of miR-140 and miR-195 mediates the teratogenicity of maternal diabetes by
suppressing Mfn1 and Mfn2, thereby altering mitochondrial dynamic and resulting in cellular
dysfunction in cells essential for cardiac septation leading heart defect formation. Moreover, the
teratogenic ASK1-JNK1/2-pathway is responsible for the miR-140 and miR-195 up-regulation, and miR-
140 and miR-195 are up-regulated in CHD-affected human diabetic pregnancies. Aim1 will determine
the roles of miR-140 and miR-195 in mediating the teratogenicity of maternal diabetes leading to
congenital heart defects. We hypothesize that both miR-140 and miR-195 contribute to the teratogenicity of
diabetes in the developing heart by inducing apoptosis and suppressing cell proliferation. Moreover, we posit
that these two miRNAs could serve as potential predictors of defective heart formation in diabetic pregnancies.
Aim 2 will investigate the mechanisms whereby the ASK1-JNK1/2-FoxO3a pathway causes CHDs and
up-regulates miR-140 and miR-195 in the developing heart. Our working hypothesis is that the oxidative
stress-activated kinase signaling, the ASK1-JNK1/2 pathway, up-regulates miR-140 and miR-195 via distinct
mechanisms. Aim 3 will To determine whether restoring the miRNA target genes mitofusin 1 and 2
expression mitigates the alteration of mitochondrial dynamics and thus alleviates heart defects in
diabetic pregnancy. Our hypothesis is that Mfn1 and Mfn2 are target genes of miR-140 and miR-195,
respectively. We postulate that down-regulation of Mfn1 and Mfn2 inhibits mitochondrial fusion, thereby leading
to mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, impaired cell proliferation and causing
CHDs. Elucidating the key miRNAs that mediate the teratogenicity of the oxidative stress-induced kinase
signaling will provide mechanistic insights of the cellular stress pathway.
.

## Key facts

- **NIH application ID:** 9922996
- **Project number:** 5R01HL134368-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jian-Ying Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $604,001
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922996

## Citation

> US National Institutes of Health, RePORTER application 9922996, MicroRNA-Suppressed Mitochondrial Fusion in Mediating the Teratogenicity of Maternal Diabetes Leading to Heart Defects (5R01HL134368-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9922996. Licensed CC0.

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