Benefits of nicotinamide in placental development and in preeclamsia

烟酰胺对胎盘发育和先兆子痫的益处

基本信息

批准号：
10298632
负责人：
Feng Li
金额：
$ 42.4万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298632
关键词：
3-Dimensional Abnormal placentation Affect Albumins Amides Angiogenic Factor Blood Pressure Blood Vessels Cell Differentiation process Cells Code Coitus Conditioned Culture Media Cone Data Decidual Cell Reactions Development Differentiation Antigens Dose EDN1 gene Embryo Endometrial Endometrial Stromal Cell Endothelin-1 Excretory function Fetal Growth Retardation Fetus Genes Genetic Genetic Polymorphism Genotype Health Human Impairment Intervention Late pregnancy Link Maternal Mortality Mediating Mediator of activation protein Medical Messenger RNA Mission Molecular Morphology Mothers Mus Niacinamide Organ Outcome Oxygen Pathogenesis Pathway interactions Peptides Peripheral Pharmacology Phenotype Placenta Placentation Play Pre-Eclampsia Pregnancy Pregnancy Outcome Premature Birth Prevention strategy Preventive Proteins Proteinuria Reporting Research Risk Role Side Single Nucleotide Polymorphism Site Stromal Cells Structure Symptoms System Testing Therapeutic Transforming Growth Factors United States National Institutes of Health Uterus Vascular Endothelial Growth Factors Viral Vitamins Weight Work angiogenesis cell motility disability drinking water fetal genetic association implantation improved in vivo inhibitor/antagonist insight maternal morbidity maternal serum mortality mouse model natural Blastocyst Implantation neonatal morbidity offspring overexpression perinatal morbidity pregnancy hypertension pregnant prevent receptor small molecule stem stem cell differentiation treatment strategy trophoblast trophoblast stem cell two-dimensional ubiquitin-protein ligase urinary

项目摘要

Summary/Abstract The molecular mechanism of pathogenesis of preeclampsia (PE) is largely unknown, and effective prevention and treatment strategies remain elusive. PE is a pregnancy-associated hypertensive condition and complicates approximately one in 20 pregnancies in the US and is a leading cause of pregnancy-related maternal mortality and neonatal morbidity/mortality worldwide. Endothelin-1 (ET-1) is a vasoconstrictive peptide of 21 residues, and single nucleotide polymorphisms (SNPs) in EDN1, coding for a precursor for ET-1, are associated with PE. Edn1H/+ mice in which Edn1 expression is elevated to 3X normal have normal blood pressure, despite elevated circulating ET-1. However, Edn1H/+ dams develop full spectrum of PE-like phenotypes in their late pregnancy. In addition, the embryos from Edn1H/+ dams, regardless of their Edn1 genotypes, lag in development during early implantation stage with disoriented ectoplacental cones. We reported that nicotinamide (amide form of vitamin B3, Nam), inhibitor of ET-1 downstream of ADP ribosylcyclase, ameliorates the PE-like phenotypes in two separate mouse models of PE, and our preliminary data show that Nam decreases urinary albumin excretion and increases the number of survival fetuses when Edn1H/+ dams were treated during the entire pregnancy. These observations have led us to hypothesize that PE in Edn1H/+ dams originates from abnormal placentation caused by a high maternal ET-1 expression at early implantation stage, and that Nam can correct this damage and protect dams from later PE development. Accordingly, Specific Aim 1 will test this hypothesis by dissociating early effects from later effects of Nam on PE of Edn1H/+dams by treatments with this vitamin starting at different gestational stages and for different durations. Pregnancy outcomes including blood pressure, urinary albumin and fetal number and weight will be determined at 18.5 day post coitus (dpc). In addition, the expression of components of ET-1 system and Nam’s effects on them at implantation stage will be examined. Specific Aim 2 will investigate the mechanism of effects of ET-1 and Nam on differentiation from human trophoblast stem cells into designated trophoblast cells by using 2- and 3- dimension culture system. Pharmacological dose of ET-1 alone, or ET-1 plus Nam will be added to the specific conditioned medium. Cells will be examined by their morphology, motility, and expression of markers of different types of trophoblasts. Specific Aim 3 will investigate the mechanism of effects of ET-1 and Nam on impaired uterine decidualization and angiogenesis. The markers of endometrial stomal differentiation, the structure of blood vessels and the expression of vascular endothelial growth factor (VEGF) in uteri at the implantation stage of pregnancy will be examined. Primary cultured endometrial stromal cells will be treated with pharmacological dose of ET-1 alone, or ET-1 plus Nam, and the markers of differentiation and the expression of VEGF will be determined. The proposed research will broaden and deepen our understanding regarding the role of the maternal genetic factor ET-1 on PE and identify a potential intervention strategy for PE.

摘要/摘要先兆子痫（PE）发病的分子机制尚不清楚，有效的预防 PE 是一种与妊娠相关的高血压疾病和并发症，治疗策略仍然难以捉摸。在美国，大约有二十分之一的妊娠发生，是与妊娠相关的孕产妇死亡的主要原因内皮素-1 (ET-1) 是一种 21 个残基的血管收缩肽， EDN1（编码 ET-1 的前体）中的单核苷酸多态性 (SNP) 与 PE 相关。 Edn1 表达升高至正常值 3 倍的 Edn1H/+ 小鼠血压正常，尽管 Edn1 表达升高然而，Edn1H/+ 母鼠在妊娠后期会形成全谱的 PE 样表型。此外，来自 Edn1H/+ 水坝的胚胎，无论其 Edn1 基因型如何，在发育过程中都会滞后。我们报道了烟酰胺（烟酰胺的酰胺形式）。维生素 B3 (Nam) 是 ADP 核糖基环化酶下游 ET-1 的抑制剂，可改善 PE 样表型两个独立的 PE 小鼠模型，我们的初步数据表明 Nam 降低尿白蛋白当在整个过程中对 Edn1H/+ 母鼠进行处理时，其排泄并增加了存活胎儿的数量。这些观察结果使我们认识到 Edn1H/+ 母鼠的 PE 源于异常。着床早期母体 ET-1 高表达引起的胎盘形成，Nam 可以纠正因此，具体目标 1 将对此进行测试。通过将 Nam 对 Edn1H/+ 水坝的 PE 的早期影响与后期影响分离出来的假设维生素从不同妊娠阶段开始并持续不同的妊娠结局，包括血液。血压、尿白蛋白以及胎儿数量和体重将在性交后 18.5 天 (dpc) 测定。此外，ET-1系统各成分的表达以及Nam在植入阶段对其的影响将具体目标 2 将研究 ET-1 和 Nam 对分化的影响机制。通过使用 2 维和 3 维培养将人滋养层干细胞转化为指定的滋养层细胞单独的 ET-1 或 ET-1 加 Nam 的药理剂量将添加到特定条件下。将通过细胞的形态、运动性和不同类型标记的表达来检查细胞。具体目标 3 将研究 ET-1 和 Nam 对受损子宫的影响机制。子宫内膜造口分化、血液结构的标志物。着床期子宫内血管及血管内皮生长因子（VEGF）的表达将检查原代培养的子宫内膜基质细胞是否怀孕。单独使用 ET-1 或 ET-1 加 Nam 的剂量，分化标志物和 VEGF 的表达将是所提议的研究将扩大和加深我们对该作用的理解。母体遗传因素 ET-1 对 PE 的影响，并确定了 PE 的潜在干预策略。