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

摘要 MiRNAs是一类抑制基因表达的非编码小RNA，在胚胎发育过程中起着至关重要的作用 心脏生成。我们发现，母亲糖尿病上调了两个miRNAs：miR-140和miR-195，它们 在成人心脏病的病理学上始终通力合作。这个目前的项目验证了这样一个假设： MiR-140和miR-195上调通过以下途径介导母体糖尿病的致畸作用 抑制Mfn1和Mfn2，从而改变线粒体动力学，导致细胞 心脏间隔所必需的细胞功能障碍导致心脏缺陷的形成。此外， 致畸的ASK1-JNK1/2通路负责miR-140和miR-195的上调，miR-140和miR-195的上调是通过致畸的ASK1-JNK1/2途径实现的。 140和miR-195在受冠心病影响的人类糖尿病妊娠中上调。Aim1将确定 MiR-140和miR-195在糖尿病致畸中的作用 先天性心脏缺陷。我们推测miR-140和miR-195都参与了小鼠的致畸作用。 糖尿病通过诱导细胞凋亡和抑制细胞增殖在发育中的心脏中的作用。此外，我们假设 这两个miRNAs可以作为糖尿病妊娠心脏形成缺陷的潜在预测因子。 目的2将研究ASK1-JNK1/2-FOXO3a通路导致CHDS和 上调发育中心脏中miR-140和miR-195的表达。我们的工作假设是，氧化剂 应激激活的激酶信号通路ASK1-JNK1/2通过不同的途径上调miR-140和miR-195 机械装置。目标3将确定是否恢复miRNA目标基因有丝分裂素1和2 表达减轻线粒体动力学改变，从而减轻心脏缺陷 糖尿病妊娠。我们的假设是Mfn1和Mfn2是miR-140和miR-195的靶基因， 分别进行了分析。我们推测，Mfn1和Mfn2的下调抑制了线粒体的融合，从而导致 使线粒体功能障碍、内质网应激、细胞凋亡、细胞增殖受损而引起 CHDS。介导氧化应激诱导的激酶致畸的关键miRNAs的阐明 信号将提供对细胞应激途径的机械性洞察。 。

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. .