Maternal Diabetes-Suppressed Vascular Signaling Induces Vasculopathy and Neural Tube Defects

母亲糖尿病抑制的血管信号传导导致血管病变和神经管缺陷

基本信息

批准号：
9080869
负责人：
Peixin Yang
金额：
$ 51.97万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9080869
关键词：
Adverse effects Age American Apoptosis BMP4 Binding Blood Island Blood Vessels Cellular Stress Complications of Diabetes Mellitus Congenital Abnormality CpG Islands Cytosine DNA DNA Methylation Data Defect Development Diabetes Mellitus Disease Down-Regulation Embryo Endoderm Epigenetic Process Event Exposure to FGF2 gene Gene Deletion Gene Silencing Health Hydralazine Hyperglycemia Hypermethylation In Situ In Vitro Individual KDR gene MAPK8 gene Mediating Methylation Monitor Mus Neural Tube Defects Neural tube Neuroepithelial Cells Organ Oxidative Stress Pathogenesis Pregnancy in Diabetics Prevention Process Recombinants Role Series Signal Transduction Staging System Testing Therapeutic Intervention Transgenic Mice Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Woman Work Yolk Sac density diabetic diabetic embryopathy endoplasmic reticulum stress fetal glycemic control inhibitor/antagonist mRNA Expression maternal diabetes novel overexpression prevent progenitor promoter protein expression public health relevance reproductive targeted treatment transcription factor type I and type II diabetes vascular factor vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Congenital malformations occur in up to 10% of babies born to diabetic women. While hyperglycemia of maternal diabetes targets multiple organs, embryonic vasculature is the first system to be developed and is most vulnerable. Diabetes induces embryonic vasculopathy leading to embryonic lethality or neural tube defects (NTD). Maternal diabetes induces the reduction and apoptosis in vascular Flk1+ progenitors and reduces blood island numbers resulting in aberrant vasculogenesis. Our preliminary data suggest that correcting altered vascular signaling and vasculopathy leads to reduced NTD formation. We hypothesize that maternal diabetes-induced DNA hypermethylation causes the downregulation of FGF2 and BMP4, which enhances VEGFR1 expression leading to impaired VEGFR2 signaling, and that these events concomitantly result in vascular Flk1+ progenitor loss and vasculopathy. Reducing vasculopathy by restoring either FGF2 or BMP4 expression relieves cellular stress and blocks JNK1/2 and apoptosis in neuroepithelial cells leading to decreased NTD formation. Restoring both FGF2 and BMP4 expression prevents vasculopathy and NTD. Aim 1 will determine the role of DNA hypermethylation in vascular gene silencing that leads to vasculopathy and NTD formation. Our working hypothesis is that DNA hypermethylation contributes to vascular gene silencing, and that the major causal factor in diabetic embryopathy, oxidative stress is responsible for DNA hypermethylation and vascular gene silencing. Aim 2 will determine whether FGF2 reduction-induced vasculopathy causes NTD formation. We hypothesize that diabetes-suppressed FGF2 expression causes Flk1+ progenitor loss and impaired VEGFR2 signaling leading to vasculopathy and consequent NTD formation. Aim 3 will determine whether restoring BMP4 expression in vasculature ameliorates vasculopathy and NTD formation. Our hypothesis is that BMP4 reduction mediates the pathogenic effect of maternal diabetes on vasculogenesis leading to NTD formation. Our application investigates novel maternal diabetes-altered vascular signaling at early development stages, proves a new concept that altered vascular signaling and resultant vasculopathy cause NTD, and overcomes existing barriers by proposing vascular Flk1+ progenitor viability and blood island formation as central steps in this disease process.

描述（由适用提供）：先天性畸形发生在糖尿病妇女出生的婴儿中多达10％。虽然母体糖尿病的高血糖靶向多个器官，但胚胎脉管系统是第一个开发的系统，最脆弱。糖尿病会诱导胚胎血管病，导致胚胎致死性或神经管缺陷（NTD）。母体糖尿病诱导血管FLK1+祖细胞的减少和凋亡，并减少血液岛的数量，导致血管生成异常。我们的初步数据表明，校正改变的血管信号传导和血管病会导致NTD形成减少。我们假设物物糖尿病诱导的DNA高甲基化会导致FGF2和BMP4的下调，从而增强了VEGFR1的表达，从而导致VEGFR2信号受损，并且这些事件同时导致血管flk1+祖细胞丧失和血管病。通过恢复FGF2或BMP4表达来减少血管病，可挽救细胞应激并阻止JNK1/2和神经上皮细胞中的凋亡，从而改善了NTD的形成。恢复FGF2和BMP4表达可防止血管病和NTD形成。 AIM 1将确定DNA高甲基化在导致血管病和NTD形成的血管基因沉默中的作用。我们的工作假设是，DNA高甲基化有助于血管基因沉默，并且糖尿病胚胎病的主要因子因素是氧化应激，导致DNA高甲基化和血管基因沉默。 AIM 2将确定FGF2还原诱导的血管病是否导致NTD形成。我们假设被糖尿病抑制的FGF2表达会导致FLK1+祖细胞丢失，而VEGFR2信号传导受损，导致血管病和随之而来的NTD形成。 AIM 3将确定恢复脉管系统中的BMP4表达是否可以改善血管病和NTD的形成。我们的假设是，BMP4还原介导了母体糖尿病对导致NTD形成的血管糖尿病的致病作用。我们的应用程序调查了早期发育阶段的新型母体糖尿病的血管信号传导，证明了一种新概念，可以改变血管信号传导和导致的血管病会导致NTD，并通过提出血管FLK1+祖细胞活力和血液岛形成这种疾病过程的步骤来克服现有障碍。