Complement Activation and Hypertensive Diseases of Pregnancy

补体激活与妊娠高血压疾病

• 批准号: 8243923
• 负责人: ANNE M. LYNCH
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243923
• 关键词: Address; American Heart Association; Antigen-Antibody Complex; Antiphospholipid Syndrome; Apoptotic; Attenuated; Biological Markers; Blood Vessels; Blood specimen; Cardiovascular Diseases; Cells; Chronic; Colorado; Complement; Complement Activation; Complement Inactivators; Data; Databases; Decidua; Development; Disease; Enzymes; Evaluation; Event; Exploratory/Developmental Grant; Freezing; Functional disorder; Funding; Growth; HELLP Syndrome; Hemolysis; Hospitals; Human; Hypertension; Hypertension induced by pregnancy; Immune; Immune system; Infection; Inflammation; Inflammatory; Life; Light; Link; Literature; Liver; Longitudinal Studies; Marines; Maternal Mortality; Measures; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Modeling; Morbidity - disease rate; Mothers; Mus; Mutation; Natural History; Necrosis; Neonatal; Outcome; Pathogenesis; Pathway interactions; Perinatal; Placenta; Plasma; Platelet Count measurement; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Preventive Intervention; Proteins; Public Health; Recording of previous events; Recruitment Activity; Reporting; Research; Research Design; Risk; Risk Factors; Role; Sampling; Series; Testing; Therapeutic; Time; Translating; United States National Institutes of Health; Universities; Variant; Vascular Diseases; Visit; Woman; cohort; combat; complement pathway; complement system; detector; fetal; genetic regulatory protein; inflammatory marker; modifiable risk; normotensive; novel; novel therapeutic intervention; pregnant; prenatal

DESCRIPTION (provided by applicant): Preeclampsia and gestational hypertension are associated with an increased risk of adverse prenatal outcomes. Altered immune-mediated inflammatory events in the placenta contribute to the pathogenesis of these hypertensive diseases of pregnancy. The complement system, a component of the innate immune system is a series of over 30 proteins that combats infection and removes immune complexes as well as ischemic, necrotic and apoptotic cells. An intact complement system is important in pregnancy. Novel research from marine models of the antiphospholipid antibody syndrome and spontaneous fetal loss has shown that complement activation in the deciduas is a major effectors for both intra-uterine fetal loss and intra-uterine growth restriction. We have translated these important findings into a study in human pregnancy, the Denver Complement Study. This study - the first to examine the role of the complement pathways in early pregnancy - made the important original discovery that elevated levels of complement activation fragments in a single plasma sample drawn at less than 20 weeks' gestation are significantly associated with an increased risk of gestational hypertension and preeclampsia later in pregnancy. In this proposed study we propose to move this research forward to address the important question of the natural history of complement activation fragments measured longitudinally in pregnancy and their links with gestational hypertension-preeclampsia. These questions have not been previously addressed in a prospectively studied pregnant cohort. We have developed the following specific aim: To determine the association between complement activation fragments measured at multiple time points in gestation with subsequent development of hypertensive diseases of pregnancy in a longitudinal study design. We will recruit a cohort of 600 ethnically and racially diverse pregnant women and follow them prospectively during pregnancy with sequential blood samples for the complement activation fragments. This research will identify a new inflammatory marker of hypertensive diseases of pregnancy. If our hypothesis is proven there may be therapeutic implications as several complement inhibitors are now available that target various components of the complement system thus modifying the effects of the inflammatory cascade. PUBLIC HEALTH RELEVANCE: Preeclampsia and gestational hypertension are associated with an increased risk of adverse prenatal outcomes. This project has the potential to identify new complement biomarkers for hypertensive diseases of pregnancy. The results of the study may ultimately hasten the development of new therapeutic interventions for this adverse pregnancy outcome.

描述（由申请人提供）：先兆子痫和妊娠期高血压与不良产前结局风险增加相关。胎盘中免疫介导的炎症事件的改变有助于这些妊娠高血压疾病的发病机制。补体系统是先天免疫系统的组成部分，是一系列超过30种蛋白质，其对抗感染并去除免疫复合物以及缺血性、坏死和凋亡细胞。完整的补体系统在怀孕中很重要。来自抗磷脂抗体综合征和自发性胎儿丢失的海洋模型的新研究表明，蜕膜中的补体激活是子宫内胎儿丢失和子宫内生长受限的主要影响因素。我们已经将这些重要的发现转化为人类妊娠的研究，丹佛补体研究。这项研究-第一次检查补体途径在早期妊娠中的作用-取得了重要的原始发现，即在妊娠不到20周时抽取的单个血浆样本中补体激活片段水平升高与妊娠后期妊娠高血压和先兆子痫的风险增加显著相关。在这项拟议的研究中，我们建议将这项研究向前推进，以解决在妊娠中纵向测量的补体激活片段的自然史及其与妊娠高血压-先兆子痫的联系的重要问题。这些问题以前没有在前瞻性研究的妊娠队列中得到解决。我们已经制定了以下具体目标：在一项纵向研究设计中，确定在妊娠多个时间点测量的补体激活片段与妊娠期高血压疾病随后发展之间的关联。我们将招募一组600名不同种族和人种的孕妇，并在怀孕期间前瞻性地随访她们，连续采集血液样本进行补体激活片段检测。本研究将为妊娠期高血压疾病提供一种新的炎症标志物。如果我们的假设得到证实，可能会有治疗意义，因为现在有几种补体抑制剂可以靶向补体系统的各种成分，从而改变炎症级联反应的影响。 公共卫生相关性：先兆子痫和妊娠期高血压与不良产前结局风险增加相关。该项目有可能为妊娠期高血压疾病确定新的补体生物标志物。这项研究的结果最终可能会加速这种不良妊娠结局的新治疗干预措施的开发。