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（APS）是一种自身免疫性疾病，其特征是产生抗磷脂抗体 (aPL) 可促进不良妊娠结局，包括胎儿流产、早产出生、宫内生长受限（IUGR）和妊娠期母亲高血压。肝素治疗可提高复发性流产 APS 患者的活产率、妊娠并发症仍然很高，因此迫切需要更有效的基于机制的治疗。之前我们发现怀孕小鼠体内普遍缺乏载脂蛋白 E 受体 2 (apoER2)。避免使用从 APS 患者身上分离出的 aPL 引起的胎儿流产和 IUGR。还在培养的滋养层中发现，通过识别细胞表面蛋白 β2GPI 及其相互作用与 apoER2 一起，aPL 抑制刺激性 Akt 磷酸化，导致细胞增殖和迁移减少。最近，我们发现 aPL 能有效激活丝氨酸/苏氨酸蛋白磷酸酶 2A (PP2A) 在体内小鼠胎盘和离体人胎盘外植体中培养人滋养层。发现 PP2A 抑制剂斑蝥素可防止 aPL 对培养滋养层细胞生长的抑制作用基于这些新颖的发现，拟议项目的总体目标是确定如何迁移。 aPL 通过滋养层功能受损导致胎儿流产、IUGR 和孕产妇高血压，并测试针对这些机制的新干预措施是否可以改善妊娠结局。 1 将确定滋养层 apoER2 及其衔接分子是否以及如何促进 aPL 诱导使用体内滋养层特异性功能丧失小鼠模型和人类滋养层进行胎儿丢失和 IUGR 目标 2 将使用体内方法研究滋养层 PP2A 在 aPL 诱导的胎儿丢失和 IUGR 中的作用。我们还将鉴定小鼠的滋养层基因和药理学功能丧失方法。通过体内 PP2A 激活受到 aPL 治疗的影响，使用我们最近建立的方法在小鼠体内选择性分离核糖体相关 RNA，目标 3 将阐明 aPL 如何诱导母体。最近我们确定 aPL 给药会促进怀孕小鼠的高血压。 aPL 刺激培养的滋养层细胞分泌可溶性 Flt-1 (sFlt-1) 和可溶性内皮糖蛋白 (sEng) 我们将确定是否刺激 sFlt-1/sEng 分泌。滋养细胞中 apoER2-PP2A 的 aPL 激活引起的血压升高是血压升高的基础，使用滋养层特异性缺失 apoER2、PP2A 或 sFlt-1/sEng 的小鼠我们还将测试 aPL 是否诱导。可以通过施用独特的单克隆抗 β2GPI 阻断剂来预防母体高血压我们确定的抗体可以防止 aPL 引起的胎儿流产，或者 PP2A 抑制剂将实现这些目标。有助于更好地了解产科 APS 的发病机制和基于机制的开发保护胎儿和母亲免受这种可能危及生命的疾病的治疗。