S.japonicum, anemia, and iron transport in human pregnancy

日本血吸虫、贫血和人类妊娠中的铁转运

• 批准号: 8839709
• 负责人: JENNIFER F FRIEDMAN
• 金额: $ 19.88万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839709
• 关键词: Address; Affect; Aftercare; Anemia; Anemia due to Chronic Disorder; Antigens; Area; Binding; Biology; Birth; Birth Weight; Carrier Proteins; Cells; Communicable Diseases; Confocal Microscopy; Data; Developed Countries; Diagnostic; Endowment; Erythroid Progenitor Cells; Etiology; Ferritin; Fetus; Funding; Goals; Grant; Growth; HIV; Health; Hemoglobin; Human; Infant; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Iron; Iron deficiency anemia; Lead; Life; Malaria; Maternal-Fetal Exchange; Measures; Mediating; Messenger RNA; Modeling; Molecular; Neonatal; Neonatal Anemia; Newborn Infant; Outcome; Pathogenesis; Pathway interactions; Persons; Philippines; Placebos; Placenta; Play; Praziquantel; Pregnancy; Pregnancy Outcome; Pregnant Women; Prevalence; Process; Public Health; Randomized Controlled Trials; Research; Risk; Role; Sampling; Schistosoma; Schistosoma japonicum; Sensitivity and Specificity; Serum; Side; Signal Transduction; Structure of umbilical artery; Techniques; Tissues; Transferrin Receptor; United States National Institutes of Health; Veins; Western Blotting; Woman; Work; World Health Organization; absorption; adverse outcome; burden of illness; cost effective; design; effective intervention; egg; falls; fetal; hepcidin; immunogenic; improved; in utero; inflammatory marker; innovation; iron supplementation; laser capture microdissection; metal transporting protein 1; novel; randomized trial; tool; trafficking; uptake; zinc protoporphyrin

DESCRIPTION (provided by applicant): The World Health Organization (WHO) estimates that nearly half of pregnant women worldwide suffer from anemia, with 52% residing in lesser-developed countries (LDCs). Despite the enormous global burden of disease due to anemia, there is a paucity of data addressing specific causes of anemia during pregnancy, and how these influence both maternal and newborn outcomes. In fact, there is little data to support the efficacy of pre-natal iron supplementation to improve pregnancy outcomes. In malaria-endemic areas, an iron replete state may actually increase risk to pregnant women and newborns. The design of cost-effective interventions to modify this enormous burden of disease depends on examining and quantifying the role of specific causes of maternal anemia. This study will begin to fill these lacunae by clearly defining the two most common causes of anemia in LDCs, iron deficiency and anemia of inflammation (AI), and relating these to pregnancy outcomes. Recent studies have demonstrated the important role of AI in the pathogenesis of anemia in pregnancy in LDCs, where a host of infectious diseases lead to ongoing inflammation. Inflammation, in turn, leads to alterations in iron absorption and distribution, ultimately limiting iron delivery t host tissues. This study will address the novel hypothesis that AI will decrease delivery of iron t the developing fetus 1) by limiting iron delivery to the placenta and 2) through fetal hepcidin elaboration which will decrease ferroportin expression and limit iron uptake. This proposal will utilize samples from an ongoing NIH funded randomized controlled trial of S. japonicum treatment in pregnancy to address the role of iron deficiency anemia and AI in mediating adverse pregnancy outcomes. AI is the primary cause of anemia in the context of S. japonicum. This study, therefore, provides the unique opportunity to examine how amelioration of AI influences pregnancy outcomes. This proposal will leverage the extensive data being collected to quantify the role of AI in adverse pregnancy outcomes and investigate potential mechanisms. The specific goals of this study are to: 1) carefully define the etiology of anemia and relate thi to maternal and newborn outcomes, 2) examine the sensitivity and specificity of novel iron and inflammatory bio-markers with respect to their ability to capture newborn risk of anemia and iron insufficiency, 3) examine how these two causes of maternal anemia affect iron delivery to placental tissues using confocal microscopy, Laser Capture Microdissection, Western blot, and qPCR techniques to quantify placental iron transport proteins, 4) understand how amelioration of maternal and fetal AI improves maternal and newborn outcomes. Given iron deficiency anemia and AI are the two leading causes of anemia in pregnancy, and interventions to address these are vastly different, understanding how each etiology affects pregnancy outcomes and developing diagnostic tools to differentiate them are of paramount importance.

描述（由申请人提供）：世界卫生组织 (WHO) 估计，全球近一半的孕妇患有贫血，其中 52% 居住在欠发达国家 (LDC)。尽管贫血给全球带来了巨大的疾病负担，但关于妊娠期贫血的具体原因以及这些原因如何影响孕产妇和新生儿结局的数据却很少。事实上，几乎没有数据支持产前补铁改善妊娠结局的功效。在疟疾流行地区，铁充足状态实际上可能会增加孕妇和新生儿的风险。 设计具有成本效益的干预措施来减轻这一巨大的疾病负担取决于检查和量化孕产妇贫血的具体原因的作用。这项研究将通过明确界定最不发达国家贫血的两种最常见原因——缺铁和炎症性贫血（AI），并将其与妊娠结局联系起来，开始填补这些空白。最近的研究证明了人工智能在最不发达国家妊娠期贫血发病机制中的重要作用，在这些国家，许多传染病会导致持续的炎症。炎症反过来会导致铁吸收和分布的改变，最终限制铁向宿主组织的输送。这项研究将提出一个新的假设，即人工智能将减少发育中胎儿的铁输送：1）通过限制铁向胎盘的输送，2）通过胎儿铁调素的精制，这将减少铁转运蛋白的表达并限制铁的吸收。 该提案将利用 NIH 资助的一项妊娠期日本血吸虫治疗随机对照试验的样本来解决缺铁性贫血和 AI 在介导不良妊娠结局中的作用。 AI 是日本血吸虫贫血的主要原因。因此，这项研究提供了独特的机会来研究人工智能的改善如何影响妊娠结局。该提案将利用收集的大量数据来量化人工智能在不良妊娠结局中的作用并调查潜在机制。本研究的具体目标是：1）仔细定义贫血的病因并将其与孕产妇和新生儿结局联系起来，2）检查新型铁和炎症生物标志物在捕获新生儿风险方面的敏感性和特异性3) 使用共聚焦显微镜、激光捕获显微切割、蛋白质印迹和 qPCR 技术检查这两种导致母体贫血的原因如何影响铁向胎盘组织的输送，以量化胎盘铁转运蛋白，4) 了解母体和胎儿 AI 的改善如何改善母体和新生儿的结局。 鉴于缺铁性贫血和人工智能是妊娠期贫血的两个主要原因，解决这些问题的干预措施截然不同，因此了解每种病因如何影响妊娠结局并开发诊断工具来区分它们至关重要。