Molecular Signalling Pathways and Cellular Stress in Diabetic Embryopathy

糖尿病胚胎病的分子信号通路和细胞应激

• 批准号: 10189679
• 负责人: E. Albert Reece
• 金额: $ 49.47万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189679
• 关键词: Adult; Age; American; Apical; Apoptosis; CDKN1A gene; Cell Cycle Arrest; Cell Proliferation; Cellular Stress; Characteristics; Child; Cultured Cells; DNA Damage; Development; Diabetes Mellitus; Down-Regulation; Embryo; Embryonic Development; Epigenetic Process; Event; Exhibits; FOXO3A gene; Genes; Health; Human; Individual; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Mediating; Mediator of activation protein; MicroRNAs; Molecular; Mus; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural tube; Neuroepithelial; Neuroepithelial Cells; Non-Insulin-Dependent Diabetes Mellitus; Organ; Oxidative Stress; Oxides; Pathway interactions; Phosphotransferases; Pregnancy in Diabetics; Prevention; Reporter; Role; Side; Signal Pathway; Signal Transduction; Stress; Structural Congenital Anomalies; Teratogens; Testing; Transcription Repressor; Up-Regulation; Woman; diabetic; diabetic embryopathy; genomic locus; improved; inhibitor/antagonist; maternal diabetes; neuroepithelium; novel; offspring; overexpression; premature; programs; promoter; reproductive; response; senescence; specific biomarkers; superoxide dismutase 1

Pregestational diabetes-induced neural tube defects (NTDs) remain a significant health problem. Kinase signaling-induced cellular stress is considered to be a causal event in NTD formation. However, the cause of stress-altered developmental programming relative to neurulation remains elusive. We found that both maternal type 1 and type 2 diabetes induce premature senescence in the developing neural tube. We also observed that deleting either the p21 gene or the p27 gene, the senescence mediators, ameliorates diabetes-induced NTD formation. Additionally, deletion of the microRNA-200c/141 (miR-200c/141) locus, which induces senescence in cultured cells, abolishes the increase of senescence mediators through the downregulation of the transcriptional repressor ZEB1 and ZEB2. Diabetes-increased miR-200c/141 expression is abrogated by superoxide dismutase 1 overexpression. Thus, we hypothesize that maternal diabetes induces premature senescence in proliferative cells of the developing neuroepithelium leading to failed neural fold fusion through up-regulation of miR-200c/141 by the oxidative stress-activated ASK1-FoxO3a pathway. miR-200c/141 up-regulates senescence mediators p21 and p27 through suppression of transcription repressors, ZEB1 and ZEB2. These senescence mediators arrest cell cycle progress of proliferative apical neuroepithelial cells leading to NTDs. Aim 1 will determine the characteristics of premature senescence during neurulation and whether diabetes-induced oxidative stress is the cause of senescence in diabetic pregnancy. We hypothesize that diabetes induces p21 expression specifically in the developing neuroepithelium leading to premature senescence in inhibiting neural fold fusion, and diabetes-induced oxidative stress is responsible for the induction of senescence in proliferative apical neuroepithelial cells. Aim 2 will investigate whether the oxidative stress-activated ASK1-FoxO3a pathway increases miR-200c/miR-141 that mediates maternal diabetes-induced premature senescence and NTDs. We will examine that diabetes induces miR-200c/141 through the ASK1-FoxO3a pathway, and that miR-200c/141 deletion suppresses p21 expression through liberating ZEB1/2 expression leading to inhibition of premature senescence and NTDs. Aim 3 will determine whether p21 and p27 induce cell cycle arrest in apical neuroepithelial cells leading to premature senescence and NTD formation in diabetic pregnancy. We will test the hypothesis that both p21 and p27 mediate cell cycle arrest and premature senescence in diabetic embryopathy, and that deletion of p21 and/or p27 ameliorates senescence and NTDs. We will continue to explore the role of key kinase signaling in senescence, a new developmental program, in diabetic embryopathy and to reveal how miRNAs participates in maternal diabetes-induced senescence.

妊娠前糖尿病引起的神经管缺陷（NTDs）仍然是一个重大的健康问题。激酶信号诱导的细胞应激被认为是NTD形成的因果事件。然而，相对于神经形成的压力改变发育编程的原因仍然难以捉摸。我们发现，母亲的1型和2型糖尿病诱导发育中的神经管过早衰老。我们还观察到，删除p21基因或p27基因，衰老介质，改善糖尿病诱导的NTD形成。此外，在培养细胞中诱导衰老的microRNA-200 c/141（miR-200 c/141）基因座的缺失通过下调转录阻遏物ZEB 1和ZEB 2来消除衰老介质的增加。糖尿病增加的miR-200 c/141表达被超氧化物歧化酶1过表达废除。因此，我们假设母体糖尿病通过氧化应激激活的ASK 1-FoxO 3a途径上调miR-200 c/141，诱导发育中神经上皮细胞的增殖细胞过早衰老，导致神经折叠融合失败。miR-200 c/141通过抑制转录抑制因子ZEB 1和ZEB 2上调衰老介质p21和p27。这些衰老介质阻止增殖性顶端神经上皮细胞的细胞周期进程，导致NTD。目的1将确定神经胚形成过程中早衰的特征，以及糖尿病诱导的氧化应激是否是糖尿病妊娠衰老的原因。我们推测，糖尿病诱导p21的表达，特别是在发展中的神经上皮细胞导致过早衰老，抑制神经折叠融合，糖尿病诱导的氧化应激是负责诱导衰老的增殖性顶端神经上皮细胞。目的2研究氧化应激激活的ASK 1-FoxO 3a通路是否增加miR-200 c/miR-141介导的母体糖尿病诱导的早衰和NTDs。我们将研究糖尿病通过ASK 1-FoxO 3a途径诱导miR-200 c/141，而miR-200 c/141缺失通过释放ZEB 1/2表达抑制p21表达，从而抑制早衰和NTD。目的3将确定p21和p27是否诱导顶端神经上皮细胞的细胞周期阻滞，导致过早衰老和NTD形成糖尿病妊娠。我们将测试的假设，即p21和p27介导细胞周期停滞和过早衰老的糖尿病胚胎病，和p21和/或p27的删除改善衰老和NTDs。我们将继续探索关键激酶信号在衰老中的作用，这是一种新的发育程序，在糖尿病胚胎病中，并揭示miRNAs如何参与母体糖尿病诱导的衰老。