Molecular Basis of Pregnancy Complications in the Antiphospholipid Syndrome

抗磷脂综合征妊娠并发症的分子基础

基本信息

批准号：
10411934
负责人：
Chieko Mineo
金额：
$ 34.78万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411934
关键词：
Adaptor Signaling Protein Address Antiphospholipid Antibodies Antiphospholipid Syndrome Autoimmune Diseases Blocking Antibodies Cell Proliferation Cell Surface Proteins Cells Complex Coupling Cultured Cells Development Disabled Homolog 2 Protein Discipline of obstetrics Disease Endocytosis Endoglin Enzyme Activation Event Female Fetal Growth Retardation Fetus Focal Adhesions Functional disorder Genes Genetic Genetic Transcription Goals Heparin Human Hypertension Immunoglobulin G Impairment Incidence Intervention Knowledge Life Live Birth Mediating Medical Research Methods Methylation Modeling Molecular Mothers Mus Pathogenesis Pathogenicity Patients Pharmacology Phosphorylation Placenta Play Pregnancy Pregnancy Complications Pregnancy Outcome Pregnancy loss Pregnant Women Premature Birth Process Production Protein Dephosphorylation Protein Serine/Threonine Phosphatase Protein phosphatase Proteins Publishing RNA Recurrence Research Project Grants Ribosomes Role Series Serine Testing Therapeutic Threonine Translating United States National Institutes of Health Vascular Endothelial Growth Factor Receptor-1 Work adverse pregnancy outcome apolipoprotein E receptor 2 base beta 2-glycoprotein I blood pressure elevation cell growth cell motility combat fetal loss improved improved outcome in vivo in vivo Model inhibitor loss of function maternal hypertension migration mouse model novel overexpression pregnant prevent prophylactic protein phosphatase 2A regulatory subunit 65 kDa recruit response trophoblast

项目摘要

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of antiphospholipid antibodies (aPL) that promote adverse pregnancy outcomes including fetal loss, premature birth, intrauterine growth restriction (IUGR), and maternal hypertension during pregnancy. Whereas treatment with heparin has improved the rate of live births in APS patients with recurrent pregnancy loss, the incidence of pregnancy complications remains high. As such, more effective mechanism-based therapies are urgently needed. Previously we showed that pregnant mice globally lacking apolipoprotein E receptor 2 (apoER2) are protected from the fetal loss and IUGR induced by the administration of aPL isolated from APS patients. We also revealed in cultured trophoblasts that via recognition of the cell surface protein β2GPI and its interaction with apoER2, aPL inhibit stimulatory Akt phosphorylation, leading to decreased cell proliferation and migration. More recently, we discovered that aPL potently activate the serine/threonine protein phosphatase 2A (PP2A) in cultured human trophoblasts, in mouse placenta in vivo, and in human placental explants ex vivo. We further found that the PP2A inhibitor Cantharidin prevents aPL inhibition of cultured trophoblast cell growth and migration. Based upon these novel findings, the overall goal of the proposed project are to determine how aPL cause fetal loss, IUGR and maternal hypertension through impairment of trophoblast function, and to test whether pregnancy outcomes are improved by novel interventions directed at these mechanisms. Aim 1 will determine whether and how trophoblast apoER2 and its adaptor molecules contribute to aPL-induced fetal loss and IUGR using trophoblast-specific loss-of-function mouse models in vivo and human trophoblasts in culture. Aim 2 will investigate the role of trophoblast PP2A in aPL-induced fetal loss and IUGR in vivo using genetic and pharmacological loss-of-function approaches in mice. We will also identify the trophoblast genes impacted by aPL treatment through PP2A activation in vivo, using our recently-established method to selectively isolate ribosome-associated RNA in mice. Aim 3 will elucidate how aPL induce maternal hypertension. Recently we determined that aPL administration promotes hypertension in pregnant mice, and that aPL stimulate the secretion of soluble Flt-1 (sFlt-1) and soluble Endoglin (sEng) from cultured trophoblasts in an apoER2- and PP2A-dependent manner. We will determine whether stimulation of sFlt-1/sEng secretion caused by aPL activation of apoER2-PP2A in trophoblasts underlies the blood pressure elevation, using the mice with trophoblast specific deletion of apoER2, PP2A or sFlt-1/sEng. We will also test if aPL-induced maternal hypertension can be prevented by the administration of a unique monoclonal anti-β2GPI blocking antibody that we identified prevents aPL-induced fetal loss, or a PP2A inhibitor. Accomplishing these aims will lead to better understanding of the pathogenesis of obstetric APS and the development of mechanism-based therapies to protect the fetus, as well as the mother, from this potentially life-threatening disorder.

抗磷脂综合征（AP）是一种自身免疫性疾病，其特征是产生抗磷脂抗体（APL）促进不良妊娠结局，包括胎儿丧失，过早出生，插入器生长限制（IUGR）和怀孕期间的母亲高血压。而治疗使用肝素可以提高APS反复怀孕丧失的APS患者的活产率，这一事件怀孕并发症仍然很高。因此，更有效的基于机制的疗法迫切需要需要。以前我们表明，全球缺乏载脂蛋白E受体2（apoer2）的怀孕小鼠是受到APS患者分离的APL的施用，免受胎儿丧失和IUGR的保护。我们在培养的滋养细胞中也揭示了通过识别细胞表面蛋白β2GPI及其相互作用使用ApoER2，APL抑制刺激性AKT磷酸化，从而导致细胞增殖和迁移减少。最近，我们发现APL可能激活丝氨酸/苏氨酸蛋白磷酸酶2a（PP2A）培养的人类滋养细胞，体内小鼠胎盘中的胎盘和人体植物外植体。我们进一步发现PP2A抑制剂cantharidin可防止培养的滋养细胞细胞生长和迁移。基于这些新颖的发现，拟议项目的总体目标是确定通过滋养细胞功能损害，APL导致胎儿丧失，IUGR和母体高血压测试针对这些机制的新干预措施是否改善了妊娠结局。目的 1将确定是否以及如何以及如何以及其适配器分子有助于APL诱导的使用滋养细胞特异性的功能丧失小鼠模型在体内和人类滋养细胞中使用胎儿损失和IUGR 在文化中。 AIM 2将研究滋养细胞pp2a在使用APL诱导的胎儿损失中的作用，并使用体内IUGR 小鼠的遗传和药理功能丧失方法。我们还将确定滋养细胞基因通过我们最近建立的方法，通过pp2a激活在体内受到APL处理的影响有选择地分离小鼠核糖体相关的RNA。 AIM 3将阐明APL如何诱导母体高血压。最近，我们确定APL给药促进了怀孕小鼠的高血压，以及 APL刺激了培养的滋养细胞中固体FLT-1（SFLT-1）和固体内og（SENG）的分泌以apoer2-和pp2a依赖性方式。我们将确定SFLT-1/Seng分泌是否由滋养细胞中apoer2-pp2a的APL激活引起的是血压升高的基础具有Apoer2，PP2A或SFLT-1/Seng的滋养细胞特异性缺失的小鼠。我们还将测试APL诱导的通过给予独特的单克隆抗β2GPI阻断，可以预防母体高血压我们确定的抗体可防止APL诱导的胎儿损失或PP2A抑制剂。完成这些目标将可以更好地理解产科AP的发病机理和基于机制的发展保护胎儿以及母亲免受这种威胁生命的疾病的疗法。