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:10183277
- 负责人:
- 金额:$ 34.78万
- 依托单位:
- 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 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAntiphospholipid AntibodiesAntiphospholipid SyndromeAutoimmune DiseasesBlocking AntibodiesBlood PressureCell ProliferationCell Surface ProteinsCellsComplexCouplingCultured CellsDevelopmentDisabled Homolog 2 ProteinDiscipline of obstetricsDiseaseEndocytosisEndoglinEnzyme ActivationEventFemaleFetal Growth RetardationFetusFocal AdhesionsFunctional disorderGenesGeneticGenetic TranscriptionGoalsHeparinHumanHypertensionImmunoglobulin GImpairmentIncidenceInterventionKnowledgeLifeLive BirthMediatingMedical ResearchMethodsMethylationModelingMolecularMothersMusPathogenesisPathogenicityPatientsPharmacologyPhosphorylationPlacentaPlayPregnancyPregnancy ComplicationsPregnancy OutcomePregnancy lossPregnant WomenPremature BirthProcessProductionProtein DephosphorylationProtein Serine/Threonine PhosphataseProtein phosphataseProteinsPublishingRNARecurrenceResearch Project GrantsRibosomesRoleSeriesSerineTestingTherapeuticThreonineTranslatingUnited States National Institutes of HealthVascular Endothelial Growth Factor Receptor-1Workadverse pregnancy outcomeapolipoprotein E receptor 2basebeta 2-glycoprotein Icell growthcell motilitycombatfetal lossimprovedimproved outcomein vivoin vivo Modelinhibitor/antagonistloss of functionmaternal hypertensionmigrationmouse modelnoveloverexpressionpregnantpreventprophylacticprotein phosphatase 2A regulatory subunit 65 kDarecruitresponsetrophoblast
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)促进不良妊娠结局,包括胎儿丢失、早产
分娩、宫内生长受限(IUGR)和妊娠期母体高血压。而治疗
与肝素联合应用可提高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方法。
needed.以前我们发现,妊娠小鼠普遍缺乏载脂蛋白E受体2(apoER 2),
保护免于由施用从APS患者分离的aPL诱导的胎儿丢失和IUGR。我们
在培养的滋养层细胞中,通过识别细胞表面蛋白β2GPI及其相互作用,
与apoER 2一起,aPL抑制刺激性Akt磷酸化,导致细胞增殖和迁移降低。
最近,我们发现aPL有效地激活丝氨酸/苏氨酸蛋白磷酸酶2A(PP 2A),
培养的人滋养层、小鼠胎盘体内和人胎盘外植体离体。我们进一步
发现PP 2A抑制剂斑蝥素阻止aPL对培养的滋养层细胞生长的抑制,
迁移基于这些新的发现,拟议项目的总体目标是确定如何
aPL通过损害滋养层功能引起胎儿丢失、IUGR和母体高血压,
测试针对这些机制的新干预措施是否能改善妊娠结局。目的
1将确定滋养层apoER 2及其衔接子分子是否以及如何促进APL诱导的细胞凋亡。
使用滋养层特异性功能丧失小鼠体内模型和人滋养层细胞的胎儿丢失和IUGR
在文化中。目的2:研究滋养层细胞PP 2A在APL诱导的胎儿丢失和IUGR中的作用。
遗传和药理学功能丧失的方法。我们还将鉴定滋养层基因
通过PP 2A体内活化受到aPL治疗的影响,使用我们最近建立的方法,
选择性分离小鼠核糖体相关RNA。目的3阐明aPL是如何诱导母体
高血压最近,我们确定aPL给药促进妊娠小鼠的高血压,
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
以apoER 2和PP 2A依赖的方式。我们将确定刺激sFlt-1/sEng分泌是否
由滋养层中apoER 2-PP 2A的aPL激活引起的高血压是血压升高的基础,
滋养层特异性缺失apoER 2、PP 2A或sFlt-1/sEng的小鼠。我们还将测试APL诱导的
母体高血压可通过给予独特的单克隆抗β2GPI阻断剂来预防
我们鉴定的抗体可预防APL诱导的胎儿丢失,或PP 2A抑制剂。实现这些目标将
从而更好地了解产科APS的发病机制和发展机制为基础的
治疗,以保护胎儿,以及母亲,从这种潜在的危及生命的疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chieko Mineo其他文献
Chieko Mineo的其他文献
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{{ truncateString('Chieko Mineo', 18)}}的其他基金
A novel role of cholesterol and SR-BI in adipocyte biology
胆固醇和 SR-BI 在脂肪细胞生物学中的新作用
- 批准号:
10733720 - 财政年份:2023
- 资助金额:
$ 34.78万 - 项目类别:
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
- 批准号:
9764402 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
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
- 批准号:
10411934 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
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
- 批准号:
9922707 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
Endothelial Basis of Obesity-induced Insulin Resistance
肥胖引起的胰岛素抵抗的内皮基础
- 批准号:
10004231 - 财政年份:2016
- 资助金额:
$ 34.78万 - 项目类别:
Discovery of Novel Interventions of the Antiphospholipid Syndrome
抗磷脂综合征的新干预措施的发现
- 批准号:
8501671 - 财政年份:2011
- 资助金额:
$ 34.78万 - 项目类别:
Discovery of Novel Interventions of the Antiphospholipid Syndrome
抗磷脂综合征的新干预措施的发现
- 批准号:
8326162 - 财政年份:2011
- 资助金额:
$ 34.78万 - 项目类别:
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