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: 8077287
• 负责人: Michael Paul Triebwasser
• 金额: $ 2.64万
• 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/8077287
• 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: Preeclampsia affects up to 10% of pregnancies and directly contributes to 76,000 maternal deaths and 500,000 fetal deaths annually. There is no therapy for this condition and it necessitates delivery of the infant, often preterm with immature organ development, which predisposes to morbidity in childhood and adult life. This research into the genetic risk factors and the mechanisms of disease will fill a gap in knowledge about the insults that cause the placental dysfunction characteristic of preeclampsia and the link between placental dysfunction and maternal decompensation.

描述（由申请人提供）：先兆子痫是一种影响全球 10% 妊娠的疾病，是孕产妇死亡和发病的主要原因。目前对于这种血管痉挛、内皮损伤和全身炎症的病症尚无有效的治疗方法。来自补体成分和调节因子靶向敲除的小鼠模型、抗磷脂综合征小鼠模型以及人胎盘观察研究的数据支持补体激活与胎盘功能障碍有关。在组织病理学类似的疾病 aHUS 中，50-60% 的病例与罕见（<1% 的人群中存在杂合）功能障碍突变相关。突变体的功能缺陷已得到表征，绝大多数（超过 95%）具有符合补体激活增加或调节不良导致病理性微血栓模型的缺陷。这些发现导致对 PROMISSE 研究中一组先兆子痫患者的膜辅因子蛋白 (MCP)、补体因子 I (FI) 和补体因子 H (FH) 进行了测序（妊娠结果的预测因素：抗磷脂综合征和全身性的生物标志物）红斑狼疮）。在 40 例病例中的 7 例中发现了罕见变异，而 33 例对照中则没有发现罕见变异。其中大多数具有功能缺陷特征，并且符合 aHUS 中补体过度激活导致疾病表型的现有模型。 这项资助完成的工作将采用双管齐下的方法：对病例和对照进行有针对性的重测序，并使用原代胎盘样本、原代人滋养层细胞和滋养层细胞系进行实验，以进一步确定补体系统在先兆子痫中的作用。对 PROMISSE 患者初始群体进行靶向重测序将鉴定先兆子痫家族连锁研究涉及的基因座的基因突变，以及文献涉及的以下途径的基因突变：补体、血栓形成、细胞周期、细胞凋亡、血管生成和内皮细胞激活。我们将研究补体途径之外以及途径内的基因，因为导致补体激活的损伤是未知的，并且任何血栓前状态的倾向都有可能增加先兆子痫的风险。第二个更大的目标重测序项目将关注先兆子痫妊娠人群，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胎盘的比较将确定这两种状态之间补体激活的差异。对原代外植体和原代人类滋养层培养物的研究将有助于研究这些变化的机制，并跟踪随着时间的推移对滋养层细胞的影响。最后，滋养层培养物中的再灌注损伤对补体激活和滋养层状态细胞命运的影响将被量化并随时间推移进行跟踪。 公共卫生相关性：先兆子痫影响高达 10% 的妊娠，每年直接导致 76,000 名孕产妇死亡和 500,000 名胎儿死亡。这种情况没有治疗方法，并且需要分娩婴儿，通常是早产且器官发育不成熟，这容易在儿童期和成年后发病。这项对遗传危险因素和疾病机制的研究将填补关于导致先兆子痫胎盘功能障碍特征的损伤以及胎盘功能障碍与母亲失代偿之间联系的知识空白。