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

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症，其中52%居住在欠发达国家（LDCs）。尽管贫血造成了巨大的全球疾病负担，但关于妊娠期间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对改善妊娠结局的有效性。在疟疾流行地区，铁元素充足的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，以改变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。这项研究将开始填补这些空白，明确界定两个最常见的原因贫血在最不发达国家，缺铁和炎症性贫血（AI），并与这些妊娠结局。最近的研究表明AI在最不发达国家妊娠贫血的发病机制中起重要作用，其中许多感染性疾病导致持续的炎症。炎症反过来导致铁吸收和分布的改变，最终限制了铁向宿主组织的递送。本研究将阐述新的假设，即AI将1）通过限制铁向胎盘的递送和2）通过胎儿铁调素的加工减少铁向发育中的胎儿的递送，这将减少铁转运蛋白的表达并限制铁摄取。 这项提案将利用来自美国国立卫生研究院资助的一项正在进行的S.本研究旨在探讨缺铁性贫血和AI在介导不良妊娠结局中的作用。在S.山茱萸因此，这项研究提供了一个独特的机会来研究AI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AI在不良妊娠结局中的作用，并研究潜在的机制。这项研究的具体目标是：1）仔细定义贫血的病因并将其与母体和新生儿结果相关联，2）检查新的铁和炎性生物标志物关于其捕获新生儿贫血和铁不足风险的能力的灵敏度和特异性，3）使用共聚焦显微镜、激光捕获显微切割、蛋白质印迹，和qPCR技术来定量胎盘铁转运蛋白，4）了解母体和胎儿AI的改善如何改善母体和新生儿结局。 鉴于缺铁性贫血和AI是妊娠贫血的两大主要原因，并且解决这些问题的干预措施有很大不同，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。

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.