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

• 批准号: 10619597
• 负责人: Feng Li
• 金额: $ 41.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10619597
• 关键词: 3-Dimensional; Abnormal placentation; Affect; Albumins; Amides; Angiogenesis Inhibitors; Angiogenic Factor; Blood Pressure; Blood Vessels; Cell Differentiation process; Cells; Code; Coitus; Conditioned Culture Media; Cone; Data; Decidual Cell Reactions; Development; Differentiation Antigens; Disorientation; Dissociation; Dose; Embryo; Endometrial; Endometrial Stromal Cell; Endothelin-1; Excretory function; Fetal Growth Retardation; Fetus; Genes; Genetic; Genetic Polymorphism; Genotype; Health; Human; Impairment; Intervention; Invaded; Late Effects; Late pregnancy; Link; Maternal Mortality; Mediating; Mediator; Medical; Messenger RNA; Mission; Molecular; Morphology; Mothers; Mus; Niacinamide; Organ; Outcome; Oxygen; Pathogenesis; Pathway interactions; Peptides; Peripheral; 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; Villous; Viral; Vitamins; Weight; Work; angiogenesis; cell motility; disability; drinking water; fetal; genetic association; hypertensive; implantation; improved; in vivo; inhibitor; insight; maternal morbidity; maternal outcome; maternal serum; mortality; mouse model; natural Blastocyst Implantation; neonatal morbidity; offspring; overexpression; perinatal morbidity; pharmacologic; pregnancy hypertension; pregnant; prevent; receptor; small molecule; stem; stem cell differentiation; treatment strategy; trophoblast; trophoblast stem cell; two-dimensional; ubiquitin-protein ligase; urinary; 3-Dimensional; Abnormal placentation; Affect; Albumins; Amides; Angiogenesis Inhibitors; Angiogenic Factor; Blood Pressure; Blood Vessels; Cell Differentiation process; Cells; Code; Coitus; Conditioned Culture Media; Cone; Data; Decidual Cell Reactions; Development; Differentiation Antigens; Disorientation; Dissociation; Dose; Embryo; Endometrial; Endometrial Stromal Cell; Endothelin-1; Excretory function; Fetal Growth Retardation; Fetus; Genes; Genetic; Genetic Polymorphism; Genotype; Health; Human; Impairment; Intervention; Invaded; Late Effects; Late pregnancy; Link; Maternal Mortality; Mediating; Mediator; Medical; Messenger RNA; Mission; Molecular; Morphology; Mothers; Mus; Niacinamide; Organ; Outcome; Oxygen; Pathogenesis; Pathway interactions; Peptides; Peripheral; 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; Villous; Viral; Vitamins; Weight; Work; angiogenesis; cell motility; disability; drinking water; fetal; genetic association; hypertensive; implantation; improved; in vivo; inhibitor; insight; maternal morbidity; maternal outcome; maternal serum; mortality; mouse model; natural Blastocyst Implantation; neonatal morbidity; offspring; overexpression; perinatal morbidity; pharmacologic; pregnancy hypertension; pregnant; prevent; receptor; small molecule; stem; stem cell differentiation; treatment strategy; trophoblast; trophoblast stem cell; two-dimensional; ubiquitin-protein ligase; urinary

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）的发病机理的分子机制在很大程度上是未知的，有效的预防 和治疗策略仍然难以捉摸。 PE是一种与怀孕相关的高血压状况，使其复杂化 在美国约有20分之一的怀孕，这是与怀孕有关的遗产死亡率的主要原因 以及全球新生儿发病率/死亡率。内皮素-1（ET-1）是21种残留物的血管收缩肽， EDN1中的单个核苷酸多态性（SNP），编码ET-1的前体，与PE相关。 EDN1H/+小鼠，其中EDN1表达升高到3倍正常的血压正常，目的地升高 循环ET-1。但是，EDN1H/+大坝在妊娠晚期会形成全谱类似PE样的表型。 此外，来自EDN1H/+大坝的胚胎，无论其EDN1基因型如何 早期植入阶段，具有迷失的外部锥锥。我们报道了烟酰胺（酰胺形式的形式 维生素B3，NAM），ADP核糖基环丙酶的ET-1抑制剂，可以改善PE样表型 PE的两个单独的鼠标模型，我们的初步数据表明NAM逐渐下降白蛋白 当整个EDN1H/+大坝进行治疗时，极端并增加了生存胎儿的数量 怀孕。这些观察结果使我们假设edn1h/+大坝中的PE起源于异常 由早期植入阶段的高母体ET-1表达引起的胎盘，而NAM可以纠正 这种损坏并保护大坝免受以后的PE开发。根据，特定的目标1将测试 通过将早期影响与NAM对EDN1H/+大坝PE的后期影响分离出来的假设， 维生素从不同的妊娠期开始，始于不同的持续时间。包括血液在内的怀孕结局 压力，白蛋白和胎儿数量和体重将在COITUS（DPC）后18.5天确定。 此外，ET-1系统和NAM在植入阶段的影响的表达将 被检查。特定目标2将研究ET-1和NAM分化的影响机理 从人类滋养细胞干细胞中使用2-维培养 系统。仅ET-1的药理剂量或ET-1 Plus NAM将添加到特定条件 中等的。细胞将通过其形态，运动性和表达不同类型的标志物进行检查 滋养细胞。具体目标3将研究ET-1和NAM对子宫受损的影响机理 义词化和血管生成。子宫内膜气孔分化的标记，血液的结构 血管和血管内皮生长因子（VEGF）在植入阶段的子宫中的表达 将检查怀孕。原发性培养的子宫内膜基质细胞将用药物治疗 单独使用ET-1的剂量，或ET-1 Plus NAM，分化的标记和VEGF的表达将是 决定。拟议的研究将扩大和加深我们对 PE上的母体遗传因子ET-1并确定PE的潜在干预策略。