The Role of Complement in the Pathogenesis of Preeclampsia

补体在先兆子痫发病机制中的作用

• 批准号: 8299550
• 负责人: Michael Paul Triebwasser
• 金额: $ 4.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299550
• 关键词: Address; Adult; Affect; Alleles; Alternative Complement Pathway; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Apoptosis; Autoimmune Diseases; Biological Markers; Biology; Blood; Blood Platelets; CD46 Antigen; Candidate Disease Gene; Cell Cycle; Cell Line; Cells; Cessation of life; Characteristics; Childhood; Complement; Complement Activation; Complement Factor B; Complement Factor H; DNA Resequencing; Data; Deposition; Development; Disease; Disease Progression; Eclampsia; Endothelial Cells; Enzymes; Excision; Exposure to; Family Study; Fetal Death; Fetal Growth Retardation; Fibrin; Fibrinogen; Frequencies; Functional disorder; Genes; Grant; Hemolysis; Hemolytic-Uremic Syndrome; Histopathology; Homeostasis; Human; Hypertension; Hypoxia; Infant; Inflammation; Inflammatory Response; Injury; Kidney; Knowledge; Life; Link; Literature; Liver; Maternal Mortality; Maternal-Fetal Exchange; Measures; Mediating; Modeling; Morbidity - disease rate; Mothers; Mutation; Nutrient; Observational Study; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Pilot Projects; Placenta; Placentation; Play; Population; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Outcome; Premature Infant; Proteinuria; Regulation; Reperfusion Injury; Research; Risk; Role; Sampling; Seizures; Spiral Artery of the Endometrium; Stroke; Syndrome; Systemic Lupus Erythematosus; Thrombosis; Thrombotic Thrombocytopenic Purpura; Time; Trees; Variant; Vasospasm; Villous; Woman; Work; angiogenesis; case control; complement pathway; complement system; disease phenotype; effective therapy; genetic risk factor; mouse model; mutant; novel; research study; response; trophoblast; wasting

DESCRIPTION (provided by applicant): Preeclampsia is a disease that affects up 10% of pregnancies globally and is the leading cause of maternal mortality and morbidity. There is not currently no effective therapy for this condition of vasospasm, endothelial damage and systemic inflammation. Data from mouse models of the targeted knock outs of complement components and regulators, a mouse model of antiphospholipid syndrome, and observational studies of human placentas supports involvement of complement activation in dysfunction of the placenta. In a histopathologically similar disease, aHUS, 50-60% of cases are associated with rare (heterozygous in <1% of the population) dysfunctional mutations. The functional deficits of the mutants have been characterized and the overwhelming majority, greater than 95%, have had a deficit that fits a model of increased or poorly regulated complement activation leading pathologic microthrombi. These findings led to the sequencing of membrane cofactor protein (MCP), complement factor I (FI), and complement factor H (FH) in a group of preeclamptic patients from the PROMISSE study (Predictors of pregnancy Outcome: biomarkers In antiphospholipid Syndrome and Systemic lupus Erythematosus). Rare variants were discovered in 7 of the 40 cases and in none of the 33 controls. Most of these had their functional deficit characterized and fit the existing model in aHUS of excessive complement activation causing the disease phenotype. Work done in this grant will use a two pronged approach of: targeted resequencing of cases and controls and experiments using primary placental samples, primary human trophoblast cells and trophoblast cell lines to further identify the role of the complement system in preeclampsia. Targeted resequencing of the initial population of PROMISSE patients will identify mutations in genes at loci implicated by linkage studies of families with preeclampsia and in the following pathways implicated by the literature: complement, thrombosis, cell cycle, apoptosis, angiogenesis, and endothelial cell activation. We will look at genes outside of the complement pathway as well as those in the pathway because the insult leading to complement activation is unknown and any predisposition to a prothrombotic state has the potential to increase the risk of preeclampsia. A second, larger targeted resequencing project will look at population of preeclamptic pregnancies, not just those with an autoimmune disease. Comparisons of healthy placentas with preeclamptic placentas will identify differences in complement activation between these two states. Studies in primary explants and primary human trophoblast cultures will allow the mechanisms of these changes to be studied and the effect on trophoblast cells to be followed over time. Finally, the effect of reperfusion injury in trophoblast cultures on complement activation and trophoblast state cell fate will be quantified and followed over time.

描述（由申请人提供）：先兆子痫是一种影响全球怀孕10％的疾病，是孕产妇死亡和发病率的主要原因。目前尚无针对这种血管痉挛，内皮损伤和全身炎症的有效疗法。来自小鼠模型的数据补体组件和调节剂的目标敲击，一种抗磷脂综合征的小鼠模型以及人胎盘的观察性研究支持补体激活参与胎盘功能障碍。在组织病理学上相似的疾病中，Ahus，50-60％的病例与罕见（<1％人口的杂合子）功能障碍突变有关。突变体的功能缺陷已经被表征，绝大多数超过95％，其缺陷符合符合增加或不良调节的补体激活的模型。这些发现导致了一组Promisse研究的先验性先验性患者（妊娠结局的预测因素：抗磷脂综合征和全身性lupus erythematososus的生物标志物），在一组先前的先验性患者中进行了膜辅因子蛋白（MCP），补体因子I（FI）和补体因子H（FH）的测序。在40例中的7例中发现了罕见的变体，而在33个对照中都没有发现。其中大多数具有其功能不足的特征，并适合现有模型过度补体激活，从而导致疾病表型。在本赠款中完成的工作将采用两种统计方法：使用原发性胎盘样品，原代人滋养细胞和滋养细胞细胞系对病例和对照和实验进行针对性重新方程，以进一步识别补体系统在前宾夕化中的作用。靶向重新判处对促进患者的初始群体的靶向重新定价将确定基因基因的基因突变，这与先兆子痫的家族以及文献所涉及的以下途径有关：补体，血栓形成，细胞周期，细胞凋亡，血管生成，血管生成和内皮细胞活化。我们将研究补体途径之外的基因以及途径中的基因，因为导致补体激活的侮辱是未知的，并且对实现血栓形成状态的任何倾向都有可能增加先兆子痫的风险。第二个较大的目标重新定位项目将研究前诊所怀孕的人群，而不仅仅是患有自身免疫性疾病的人群。健康胎盘与先兆子痫的胎盘的比较将确定这两种状态之间补体激活的差异。在原代外植体和原发性滋养细胞培养物中的研究将允许研究这些变化的机制，并随着时间的推移对滋养细胞的影响。最后，将量化并随着时间的推移量化滋养细胞培养物中再灌注损伤对补体激活和滋养细胞状态细胞命运的影响。