IN VIVO AND IN VITRO MODELS OF PRE-ECLAMPSIA PATHOLOGY

先兆子痫病理学的体内和体外模型

• 批准号: 8360545
• 负责人: ZHONGBIN LAI
• 金额: $ 19.9万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360545
• 关键词: Address; Affect; Animal Model; Biological Assay; Biology; Blood Pressure; Blood Vessels; Centers of Research Excellence; Combat Disorders; Data; Defect; Development; Diagnostic; Disease; Endoglin; Endothelial Cells; Etiology; Experimental Models; Fetal Growth Retardation; Functional disorder; Funding; Grant; Human; Hypertension; In Vitro; Inflammation; Injection of therapeutic agent; Kidney; Maternal-Fetal Exchange; Mediating; Modality; Monitor; Morbidity - disease rate; Mus; National Center for Research Resources; Pathogenesis; Pathologic; Pathology; Patients; Perinatal; Pre-Eclampsia; Principal Investigator; Production; Proteinuria; Research; Research Infrastructure; Research Personnel; Resources; Serum; Source; Symptoms; System; Therapeutic; United States National Institutes of Health; Vascular Diseases; cost; design; in vitro Model; in vivo; insight; matrigel; mortality; prophylactic; trophoblast

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality but has an unknown etiology. While the precise pathophysiology is certainly multi-factorial, many investigators believe it represents a microvasculopathy with an important underlying immunopathogenesis. As such, improvements in our understanding of the pathogenesis may provide insights into other vascular disorders. The late onset of symptoms and the myriad conditions associated with its onset have impaired our ability to study this disease. This condition primarily affects humans and the establishment of an animal model has been elusive. The creation of a pre-eclamptic animal model would enhance our understanding of the pathophysiology of pre-eclampsia and contribute to the development of diagnostic, prophylactic and therapeutic modalities needed to combat this disorder. The pre-eclamptic animal model should present some or all of the hallmark features such as placental inflammation, degeneration, intrauterine growth restriction, vascular deficiency, high blood pressure, proteinuria, and kidney pathology. Since pre-eclampsia is a systemic manifestation of local defects at the maternal-fetal interface, we hypothesize that serum from these patients should provide a "blueprint" of the factors associated with these pathologic conditions. Although there is no precedent for pre-eclampsia serum to manifest any in vivo anomalies, our preliminary data demonstrates that a single injection i.p. of serum on gestational day 10 could induce elevated blood pressure, proteinuria, intrauterine growth restriction, and elevated production of soluble endoglin in wild type C57 Bl/6 mice. In addition, pre-eclampsia serum also disrupted cross talk between trophoblasts and endothelial cells as monitored in a three dimensional culture system on matrigel. To address our central hypothesis and to expand on our preliminary data, we propose the following specific aims. Specific Aim 1 is designed to assess the in vivo potential of pre-eclampsia serum from mild or severe condition to cause hallmark features of the disease in mice. In Specific Aim 2, we will determine pre-eclampsia serum-mediated disruption and rescue of cross-talk between extravillous trophoblasts and endothelial cells in an in vitro, three dimensional culture system. These studies will contribute to in vivo and in vitro experimental models to better understand mechanistic underpinnings of and to establish predictive assays for pre-eclampsia.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 先兆子痫是孕产妇和围产期发病率和死亡率的主要原因，但病因不明。虽然确切的病理生理学肯定是多因素的，但许多研究人员认为它代表了具有重要潜在免疫发病机制的微血管病变。因此，我们对发病机制的理解的提高可能会为其他血管疾病提供见解。迟发的症状和与其发病相关的无数条件削弱了我们研究这种疾病的能力。这种情况主要影响人类，动物模型的建立一直难以捉摸。 先兆子痫动物模型的建立将增强我们对先兆子痫病理生理学的理解，并有助于开发对抗这种疾病所需的诊断，预防和治疗方式。先兆子痫动物模型应呈现一些或全部标志性特征，如胎盘炎症、变性、宫内生长受限、血管缺陷、高血压、蛋白尿和肾脏病理。由于先兆子痫是母胎界面局部缺陷的全身表现，我们假设这些患者的血清应该提供与这些病理条件相关的因素的“蓝图”。虽然没有先兆子痫血清表现出任何体内异常的先例，但我们的初步数据表明，在妊娠第10天单次腹膜内注射血清可诱导野生型C57 B1/6小鼠血压升高、蛋白尿、子宫内生长受限和可溶性内皮糖蛋白产生增加。此外，先兆子痫血清也破坏了滋养层细胞和内皮细胞之间的串扰，如在基质胶上的三维培养系统中所监测的。为了解决我们的中心假设，并扩大我们的初步数据，我们提出了以下具体目标。 特定目的1旨在评估轻度或重度条件下先兆子痫血清在小鼠中引起疾病标志性特征的体内潜力。在特定目标2中，我们将在体外三维培养系统中确定先兆子痫血清介导的绒毛外滋养层细胞和内皮细胞之间串扰的破坏和拯救。这些研究将有助于在体内和体外实验模型，以更好地了解机制的基础，并建立先兆子痫的预测分析。