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

摘要 miRNAs是一类沉默基因表达的非编码小RNA，在胚胎发育过程中起着重要作用。 心脏发生我们发现母亲糖尿病上调了两种miRNAs：miR-140和miR-195， 在成人心脏病的病理学研究中总是相互协作。目前的项目测试的假设， miR-140和miR-195的上调通过以下途径介导母体糖尿病的致畸性： 抑制Mfn 1和Mfn 2，从而改变线粒体动力学并导致细胞凋亡。 心脏分隔所必需的细胞功能障碍导致心脏缺陷形成。而且 致畸性ASK 1-JNK 1/2-途径负责miR-140和miR-195的上调，而miR-140和miR-195的上调与致畸性ASK 1-JNK 1/2-途径有关。 140和miR-195在CHD影响的人类糖尿病妊娠中上调。AIM 1将决定 miR-140和miR-195在介导母体糖尿病致畸性中的作用， 先天性心脏病我们假设miR-140和miR-195都有助于致畸性。 通过诱导细胞凋亡和抑制细胞增殖来抑制糖尿病在发育中的心脏中的作用。此外，我们 这两种miRNAs可以作为糖尿病孕妇心脏形成缺陷的潜在预测因子。 目的2将研究ASK 1-JNK 1/2-FoxO 3a通路导致CHD的机制， 在发育中的心脏中上调miR-140和miR-195。我们的假设是， 应激激活的激酶信号传导，即ASK 1-JNK 1/2通路，通过不同的途径上调miR-140和miR-195， 机制等目的3：确定修复miRNA靶基因mitofusin 1和2是否能有效地抑制细胞凋亡， 表达减轻了线粒体动力学的改变，从而减轻了心脏缺陷， 糖尿病妊娠我们的假设是Mfn 1和Mfn 2是miR-140和miR-195的靶基因， 分别我们推测Mfn 1和Mfn 2的下调抑制了线粒体融合，从而导致了 线粒体功能障碍、内质网应激、凋亡、受损的细胞增殖和引起 冠心病阐明介导氧化应激诱导激酶致畸性的关键miRNAs 信号传导将提供细胞应激途径的机制性见解。 .

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. .