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：
10160931
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/10160931
关键词：
Age American Apoptosis Autophagocytosis Autophagosome Binding Binding Proteins Child Cleaved cell 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/antagonist 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.

孕育糖尿病会在后代诱导神经管缺陷（NTD）。即使是最好的产前护理，糖尿病女性患有先天缺陷的孩子比非糖尿病妇女要高三到四倍。糖尿病引起的NTD对于母亲和她的孩子都是重大的公共卫生问题。然而，尚不清楚母体糖尿病的致畸性的分子机制。最近，我们在母体糖尿病引起的自噬损伤中发现了MicroRNA介导的应激途径，导致NTD。长时间展开的蛋白质反应（UPR）和内质网（ER）应力在母体糖尿病引起的NTD中起关键作用。延长的UPR和自噬损伤之间的分子联系是弹性的。我们发现，沉默的主要UPR传感器IRE1α触发了从头自噬体的形成，并在发育中的神经上皮中删除了IRE1A基因，从而挽救了自噬，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触发IRE1α激活，而ASK1-IRE1α信号通过产生XBP1s和降解miR-17，通过IRE1αRNase活性来抑制发育中神经皮质的自噬，其靶向TXNIP。 XBP1，miR-17-TXNIP电路及其串扰介导导致NTD形成的母体糖尿病的致病性。为了检验我们的假设，我们提出了三个具体目标。 AIM 1将确定ask1激活的IRE1α是否负责糖尿病胚胎中的自噬损伤。我们假设生物糖尿病诱导的ASK1激活通过直接磷酸化触发IRE1α激活，并抑制了展开的蛋白质的ER相关降解（ERAD）。我们进一步确认，ask1-ire1α信号抑制了自噬导致NTD形成。 AIM 2将研究XBP1和miR-17之间的潜在串扰，及其在母体糖尿病引起的自噬障碍和NTD形成中的作用。我们假设IRE1α裂解XBP1 mRNA形成XBP1并反映miR-17的表达，共同导致ATG表达改变，并且XBP1S和MiR-17受到相互调节，从而导致自噬在发育中的神经上皮和NTD中的自噬受损。 AIM 3将确定TXNIP是否是我们的假设是，TXNIP是IRE1α-MIR-17途径的下游效应子TXNIP通过与ATG4在LC3-II中处理LC3-I的能力的结合，从而反映了自噬，从而反映了LC3-II中的LC3-I的能力，这是自动噬菌体形成的基本步骤，导致了Cellartial Imbiral Implysal and timallance Imbyallansy Imbys Imbys Imbys Imbys Impallansy Imbydds Imbydds Imbydds Imbydds Imbydds Imbydds Imbydds Imbydds Immimbys Imbydds Imbydds Imbydds Imbydds。