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. .
Congenital heart defects (CHDs) cause a significant impact on morbidity and mortality. Uncovering the mechanisms by which miRNAs inhibits mitochondrial fusion in maternal diabetes-induced CHDs may allow us to explore whether drugs that activate mitochondrial fusion can prevent CHDs. The miRNAs identified in this study could be valuable for early CHD diagnosis. Targeting specific miRNAs and cellular organelle stress are potential new preventive and therapeutic strategies for CHDs
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