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Autophagy and its Regulation in Diabetic Embryopathy

自噬及其在糖尿病胚胎病中的调控

基本信息

批准号：
10360659
负责人：
Peixin Yang
金额：
$ 50.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-07 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360659
关键词：
Age American Apoptosis Autophagocytosis Autophagosome Binding Binding Proteins Child Complex Congenital Abnormality Data Diabetes Mellitus Embryo Endoplasmic Reticulum Enzymes Exposure to Gene Deletion Gene Expression Genes Homeostasis Human Hyperglycemia Impairment Knockout Mice Link MAP3K5 gene Measures Mediating Messenger RNA MicroRNAs Molecular Mothers Neural Tube Defects Organelles Pathway interactions Phosphorylation Play Pregnancy in Diabetics Prenatal care Prevention strategy Process Production Proteins Public Health Regulation Ribonucleases Role Signal Transduction Stress TXNIP gene Teratogens Testing Time Transgenic Mice Transgenic Organisms Up-Regulation Woman XBP1 gene Xenopus diabetic diabetic embryopathy endoplasmic reticulum stress functional restoration glycemic control inhibition of autophagy inhibitor malformation maternal diabetes neuroepithelium non-diabetic offspring overexpression prevent reproductive response sensor therapeutic development

项目摘要

Pregestational diabetes induces neural tube defects (NTDs) in the offspring. Even under the best prenatal care, diabetic women are still three- to four-times more likely to have a child with birth defects than nondiabetic women. Diabetes-induced NTDs are significant public health problems for both the mother and her child. Yet, the molecular mechanism underlying the teratogenicity of maternal diabetes is still unclear. We recently discovered a microRNA-mediated stress pathway in maternal diabetes-induced autophagy impairment leading to NTDs. Prolonged unfolded protein response (UPR) and endoplasmic reticulum (ER) stress play critical roles in maternal diabetes-induced NTDs. The molecular link between prolonged UPR and autophagy impairment is elusive. We found that silencing the major UPR sensor, IRE1α, triggered de novo autophagosome formation, and deleting the Ire1a gene in the developing neuroepithelium rescued autophagy thereby preventing NTD in diabetic pregnancy. Therefore, we hypothesize that maternal diabetes triggers IRE1α activation through ASK1 and the ASK1-IRE1α signal inhibits autophagy in the developing neuroepithelium through IRE1α RNase activity by producing XBP1s and degrading miR-17, which targets Txnip. XBP1s, the miR-17-Txnip circuit, and their crosstalk mediate the teratogenicity of maternal diabetes leading to NTD formation. To test our hypothesis, we proposed three Specific Aims. Aim 1 will determine whether ASK1-activated IRE1α is responsible for autophagy impairment in diabetic embryopathy. We hypothesize that maternal diabetes-induced ASK1 activation triggers IRE1α activation via direct phosphorylation and suppresses ER-associated degradation (ERAD) of unfolded proteins. We further posit that the ASK1-IRE1α signal suppresses autophagy leading to NTD formation. Aim 2 will investigate the potential crosstalk between XBP1s and miR-17, and their roles in maternal diabetes-induced autophagy impairment and NTD formation. We hypothesize that IRE1α cleaves XBP1 mRNA to form XBP1s and represses miR-17 expression, collectively resulting in altered ATG expression, and that XBP1s and miR-17 are reciprocally regulated, leading to autophagy impairment in the developing neuroepithelium and NTDs in diabetic pregnancy. Aim 3 will determine whether Txnip is a target gene of the IRE1α-miR-17 pathway and participates in autophagy inhibition in diabetic embryopathy. Our hypothesis is that Txnip, a downstream effector of the IRE1α-miR-17 pathway, represses autophagy by binding to and thus disabling the ability of ATG4 in processing LC3-I in to LC3-II, an essential step for autophagosome formation, leading to cellular imbalance and NTDs in diabetic pregnancy.

妊娠期糖尿病会导致子代出现神经管缺陷。即使是在最好的产前值得注意的是，糖尿病女性生下有出生缺陷的孩子的可能性仍然是非糖尿病女性的三到四倍。糖尿病引起的NTDS对母亲和她的孩子都是重大的公共健康问题。然而，母体糖尿病致畸的分子机制仍不清楚。我们最近在糖尿病引起的自噬损害中发现了一条由microRNA介导的应激通路，从而导致NTDS。长期的未折叠蛋白反应(UPR)和内质网(ER)应激在母体糖尿病所致的NTDS中起着关键作用。延长的UPR和自噬损害之间的分子联系尚不清楚。我们发现，沉默主要的UPR感受器Ire1α，触发新的自噬形成，并删除发育中的神经上皮中的Ire1a基因，拯救了自噬，从而防止了糖尿病妊娠的NTD。因此，我们假设母体糖尿病通过ASK1激活IRE1α，而ASK1-IRE1α信号通过产生XBP1和降解针对α的miR-17，通过IRE1TXNIP核糖核酸酶活性抑制发育中的神经上皮的自噬。XBP1s、miR-17-TXNIP通路和它们的串扰介导了导致NTD形成的母亲糖尿病的致畸作用。为了验证我们的假设，我们提出了三个具体目标。目的1将确定ASK1激活的IRE1α是否与糖尿病胚胎病变的自噬损害有关。我们假设，母体糖尿病诱导的ASK1激活通过直接磷酸化触发IRE1α激活，并抑制未折叠蛋白的ER相关降解。我们进一步推测，ASK1-IRE1α信号抑制了导致NTD形成的自噬。目的2将研究XBP1和miR-17之间的潜在串扰，以及它们在母亲糖尿病引起的自噬损伤和NTD形成中的作用。我们假设IRE1α裂解XBP1mRNA形成XBP1s并抑制miR-17的表达，共同导致ATG表达的改变，并且XBP1s和miR-17是相互调节的，导致糖尿病妊娠中发育中的神经上皮和NTDS的自噬障碍。目的3将确定血栓素NIP是否是IRE1α-miR-17途径的靶基因，并参与糖尿病胚胎病变的自噬抑制。我们的假设是，IRE1α-miR-17途径的下游效应者TXNIP通过与ATG4结合从而使ATG4在处理Lc3-I进入Lc3-II的过程中失去能力来抑制自噬，这是自噬形成的关键步骤，导致细胞失衡和糖尿病妊娠中的NTDS。