Predictors of Pregnancy Outcome In SLE and APS

SLE 和 APS 妊娠结局的预测因素

• 批准号: 7931840
• 负责人: Jane E Salmon
• 金额: $ 47万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2011-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931840
• 关键词: Adult; Angiogenesis Inhibitors; Angiogenic Factor; Animals; Anti-DNA Antibodies; Antibodies; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Autoantibodies; Behavior; Biological Markers; Blood - brain barrier anatomy; Brain; Cessation of life; Child; Classical Complement Pathway; Clinical; Cognitive; Cohort Studies; Collection; Complement; Complement Activation; Complement component C1; DNA; Data; Development; Disease; Endoglin; Enrollment; Equilibrium; Etiology; Event; Exposure to; Fetal Growth; Fetal Growth Retardation; Fetus; Fostering; Functional disorder; Funding; Growth; Habitual Abortion; Heparin; Human; Impaired cognition; Infant; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Lead; Learning Disabilities; Literature; Lupus; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mothers; Mus; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurons; Observational Study; Outcome; PGF gene; Patients; Perinatal Exposure; Phenotype; Placental Growth Factor; Placental Insufficiency; Placentation; Plasma; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy loss; Premature Birth; Research; Research Infrastructure; Research Personnel; Resources; Risk; Role; Sample Size; Sampling; Spontaneous abortion; Systemic Lupus Erythematosus; Testing; Time; Tissues; Translating; Urine; Vascular Endothelial Growth Factor Receptor; Woman; Work; activation product; behavioral impairment; cohort; complement pathway; effective therapy; fetal; in vivo; injured; meetings; mortality; mouse model; neonatal morbidity; neurotoxicity; new therapeutic target; novel; offspring; pregnancy immunology; pregnant; prevent; primary outcome; prospective; stillbirth; Adult; Angiogenesis Inhibitors; Angiogenic Factor; Animals; Anti-DNA Antibodies; Antibodies; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Autoantibodies; Behavior; Biological Markers; Blood - brain barrier anatomy; Brain; Cessation of life; Child; Classical Complement Pathway; Clinical; Cognitive; Cohort Studies; Collection; Complement; Complement Activation; Complement component C1; DNA; Data; Development; Disease; Endoglin; Enrollment; Equilibrium; Etiology; Event; Exposure to; Fetal Growth; Fetal Growth Retardation; Fetus; Fostering; Functional disorder; Funding; Growth; Habitual Abortion; Heparin; Human; Impaired cognition; Infant; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Lead; Learning Disabilities; Literature; Lupus; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mothers; Mus; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurons; Observational Study; Outcome; PGF gene; Patients; Perinatal Exposure; Phenotype; Placental Growth Factor; Placental Insufficiency; Placentation; Plasma; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy loss; Premature Birth; Research; Research Infrastructure; Research Personnel; Resources; Risk; Role; Sample Size; Sampling; Spontaneous abortion; Systemic Lupus Erythematosus; Testing; Time; Tissues; Translating; Urine; Vascular Endothelial Growth Factor Receptor; Woman; Work; activation product; behavioral impairment; cohort; complement pathway; effective therapy; fetal; in vivo; injured; meetings; mortality; mouse model; neonatal morbidity; neurotoxicity; new therapeutic target; novel; offspring; pregnancy immunology; pregnant; prevent; primary outcome; prospective; stillbirth

DESCRIPTION (provided by applicant): Pregnancy complications in women with the antiphospholipid syndrome (APS) and/or SLE include recurrent miscarriage, preeclampsia, placental insufficiency, and intrauterine growth restriction (IUGR). The mechanisms leading to placental and fetal injury in vivo are incompletely understood and treatment remains sub-optimal. We have identified complement as an early effector in pregnancy loss and/or IUGR associated with placental inflammation in a mouse model of APS and shown that complement activation causes the release of anti- angiogenic factors and abnormal placental development. The PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) is a first-time effort to translate our novel findings in mice to humans and determine if elevations of complement split products predict pregnancy complications in patients with antiphospholipid (aPL) antibodies and/or SLE. In the first 4 years of this prospective, observational study of pregnant patients grouped and analyzed according to the presence or absence of aPL antibodies and preexisting SLE, we have enrolled 342 pregnant patients in 7 centers, obtained detailed medical and obstetrical information monthly, and serially collected plasma, serum, DNA, RNA, and urine. Preliminary data suggest that elevated levels of complement activation products antecede and predict poor fetal outcome, consistent with our hypothesis that complement is a proximal mediator of fetal loss and IUGR. We propose to increase our target sample size from 400 to 700 pregnant patients to maintain study power given lower than expected outcome rates, and to leverage the infrastructure and rich collection of patient data and samples by expanding the array of biomarkers and scope of adverse pregnancy outcomes. Specifically, in Aim 1 we will determine whether elevations of split products generated by activation of complement pathways predict poor fetal and/or maternal outcome in patients with aPL antibodies and/or SLE and, in Aim 2, whether the balance of circulating angiogenic and antiangiogenic factors predicts preeclampsia or delivery of IUGR infants. In Aim 3, a new direction, we will use the PROMISSE cohort to affirm in humans our recent findings in mice, that certain anti-DNA antibodies cross-react with N-methyl D- aspartate receptors (NMDAR) and cause neuronal death with ensuing cognitive and behavioral impairment. We propose to quantitate anti-NMDAR antibody levels throughout pregnancy in PROMISSE SLE patients and test the hypothesis that in utero exposure to maternal anti-NMDAR antibodies alters behavior and cognitive development in offspring by evaluating cortical function tasks in 12 month and 3.5 year old children. This competitive renewal and extension of the PROMISSE Study provides an outstanding opportunity to translate knowledge from mouse models to patients, define pathogenic mechanisms, identify predictors of poor pregnancy outcome in APL and/or SLE, and define novel therapeutic targets to prevent such outcomes.Patients with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies are at increased risk for miscarriage, preeclampsia and fetal growth restriction - major causes of maternal, fetal, and neonatal morbidity and mortality in the US and worldwide - whose etiology and mechanism remain unknown and for which therapy is limited. In addition to causing placental dysfunction, maternal autoantibodies may also directly impair fetal brain development. Identification of biomarkers that predict poor pregnancy outcome in these patients will elucidate mechanisms of disease, define targets for treating patients, and generate clinically applicable indicators to permit initiation of interventional trials in patients at greatest risk for pregnancy complications.

描述（由申请人提供）： 患有抗磷脂综合征（AP）和/或SLE的女性的妊娠并发症包括反复流产，先兆子痫，胎盘不足和宫内内生长限制（IUGR）。导致体内胎盘和胎儿损伤的机制尚不完全理解，治疗仍然是最佳的。我们已经将补体确定为AP小鼠模型中妊娠丧失和/或IUGR的早期效应子，并表明补体激活会导致抗血管生成因子释放和异常胎盘发育。 Promisse研究（妊娠结局的预测：抗磷脂抗体综合征和全身性狼疮红斑的生物标志物）是将我们在小鼠中的新颖发现转化为人类的首次努力，并确定补体分裂产物的升高是否可以预测患有抗磷脂（APL）抗体和///或sle的抗抑制性妊娠复杂性。在这项前四年的前4年中，根据APL抗体的存在或不存在APL抗体和先前存在的SLE进行分组和分析的孕妇的观察性研究，我们已经在7个中心招募了342名孕妇，每月获得详细的医疗和近亲信息，并获得了详细的医疗信息，并获得了血浆，血浆，血清，DNA，DNA，DNA，RNA和urine。初步数据表明，补体激活产物水平升高，预测胎儿预后不良，这与我们的假设是补体是胎儿损失和IUGR的近端介体。我们建议将目标样本量从400名孕妇增加到700名孕妇，以保持研究能力低于预期的结果，并通过扩大生物标志物以及不良怀孕结果的范围来利用基础设施和丰富的患者数据和样品收集。具体而言，在AIM 1中，我们将确定通过补体途径激活产生的分裂产物的升高是否可以预测APL抗体和/或SLE的患者的胎儿和/或母体结局，以及在AIM 2中，是否可以预测循环血管生成和抗基因生成因子的平衡是否可以预测iugr婴儿的先兆子痫或递送。在AIM 3（一个新的方向）中，我们将使用Promisse队列在人类中确认我们最近在小鼠中的发现，即某些抗DNA抗体与N-甲基D-天然病受体（NMDAR）交叉反应，并导致神经元死亡，并带有逐渐认知和行为障碍。我们建议在Promisse SLE患者中量化抗NMDAR抗体水平，并检验以下假设：子宫暴露于母体抗NMDAR抗体中，通过评估12个月内的皮质功能任务来改变后代的行为和认知发展。 This competitive renewal and extension of the PROMISSE Study provides an outstanding opportunity to translate knowledge from mouse models to patients, define pathogenic mechanisms, identify predictors of poor pregnancy outcome in APL and/or SLE, and define novel therapeutic targets to prevent such outcomes.Patients with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies are at increased risk for流产，先兆子痫和胎儿生长限制 - 在美国和全球范围内产妇，胎儿和新生儿发病率和死亡率的主要原因 - 其病因和机制仍然未知，并且治疗受到限制。 除了引起胎盘功能障碍外，母体自身抗体还可能直接损害胎儿脑发育。 鉴定这些患者预测妊娠不良结局的生物标志物将阐明疾病的机制，定义治疗患者的靶标，并产生临床适用的指标，以允许在患者妊娠并发症风险最大的患者中启动介入的试验。