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: 10440363
• 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/10440363
• 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; 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（NTD）仍然是一个严重的健康问题。激酶信号传导诱导的细胞应激被认为是 NTD 形成的因果事件。然而，与神经调节相关的压力改变发育程序的原因仍然难以捉摸。我们发现，母亲 1 型和 2 型糖尿病都会导致发育中的神经管过早衰老。我们还观察到，删除衰老介质 p21 基因或 p27 基因可以改善糖尿病诱导的 NTD 形成。此外，删除可诱导培养细胞衰老的 microRNA-200c/141 (miR-200c/141) 位点，可通过下调转录抑制子 ZEB1 和 ZEB2 消除衰老介质的增加。糖尿病导致的 miR-200c/141 表达增加被超氧化物歧化酶 1 过度表达所消除。因此，我们假设母亲糖尿病通过氧化应激激活的 ASK1-FoxO3a 途径上调 miR-200c/141，诱导发育中的神经上皮增殖细胞过早衰老，导致神经折叠融合失败。 miR-200c/141 通过抑制转录抑制因子 ZEB1 和 ZEB2 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，从而导致 NTD。目标 1 将确定神经发育过程中过早衰老的特征，以及糖尿病引起的氧化应激是否是糖尿病妊娠中衰老的原因。我们假设糖尿病会在发育中的神经上皮中特异性诱导 p21 表达，从而抑制神经折叠融合而导致过早衰老，而糖尿病诱导的氧化应激则负责诱导增殖性顶端神经上皮细胞的衰老。目标 2 将研究氧化应激激活的 ASK1-FoxO3a 通路是否会增加 miR-200c/miR-141，从而介导母体糖尿病诱导的早衰和 NTD。我们将研究糖尿病通过 ASK1-FoxO3a 途径诱导 miR-200c/141，并且 miR-200c/141 缺失通过释放 ZEB1/2 表达来抑制 p21 表达，从而抑制过早衰老和 NTD。目标 3 将确定 p21 和 p27 是否会诱导顶端神经上皮细胞的细胞周期停滞，从而导致糖尿病妊娠期间过早衰老和 NTD 形成。我们将检验以下假设：p21 和 p27 均介导糖尿病胚胎病中的细胞周期停滞和过早衰老，并且 p21 和/或 p27 的缺失可改善衰老和 NTD。我们将继续探索关键激酶信号传导在衰老（一种新的发育程序）中在糖尿病胚胎病中的作用，并揭示 miRNA 如何参与母体糖尿病诱导的衰老。