Pathways of Maternal Anemia

描述(申请人提供)：在热带国家，妊娠疟疾是一个巨大的公共卫生问题，它与母亲和她的孩子的疾病和死亡率有关。疟疾在初孕妇女(患有这种疾病)中引起炎症反应。在初产妇中，胎盘中高水平的肿瘤坏死因子-1与母体贫血有关，而在多胎孕妇中则不相关。我们假设，初孕妇女的促炎信号通路改变了胎盘中红细胞生成特异性因子的表达，通过以下两种途径中的一种或两种导致贫血。1.炎性细胞因子和其他巨噬细胞介质抑制调节红细胞生成的胎盘因子的表达。2.寄生虫与胎盘合体滋养层细胞的黏附直接调节调节红细胞生成的胎盘因子的表达。蛋白质组学研究构成了一种无偏见的方法来研究全球蛋白质表达的差异。在这里，我们将检测与疟疾贫血途径有关的胎盘血浆蛋白质组变化，这些变化发生在寄生虫隔离和炎症的部位-胎盘。具体地说，这项研究将检验1.利用定量蛋白质组学工具检测与疟疾贫血相关的胎盘血浆蛋白质组的变化。2.用定量蛋白质组学方法研究胎盘免疫细胞的分泌组。3.确认在坦桑尼亚妇女队列中疟疾贫血途径蛋白与疟疾贫血有关。基于这些假设，我们预计胎盘血中与红细胞生成相关的转录因子、生长因子和免疫调节剂的相对丰度将与母体血红蛋白水平相关。我们期望巨噬细胞特异的调节红系增殖和发育的介体在原发孕妇的胎盘血样本中会更加丰富。妊娠期疟疾是人们最了解的疟疾综合征。疟疾感染孕妇血浆蛋白质组的特征将有助于我们了解怀孕宿主中宿主与病原体的相互作用，并将为参与儿童严重贫血发病机制的新分子的更大范围的研究提供信息。在疟疾流行地区，孕期疟疾是孕产妇死亡的危险因素 因贫血而死亡。妊娠、疟疾和产妇贫血是低出生体重分娩的独立风险因素，增加了新生儿期和婴儿期的死亡风险。这项研究将确定潜在的免疫和转录途径以及在疟疾相关母体贫血发病机制中起关键作用的介体。

DESCRIPTION (provided by applicant): Pregnancy malaria is an overwhelming public health problem in tropical countries, which has been related to disease and mortality for both the mother and her child. Malaria induces inflammatory responses in primigravid women (who suffer from the disease). High TNF-1 levels in the placenta are associated with maternal anemia in primigravidas but not in multigravidas. We hypothesize that proinflammatory signaling pathways in primigravid women modify the expression of erythropoiesis-specific factors in the placenta, leading to anemia through one or both of the following pathways. 1. Inflammatory cytokines and other macrophage mediators suppress the expression of placental factors that regulate erythropoiesis. 2. Parasite adhesion to placental syncytiotrophoblast directly modulates the expression of placental factors that regulate erythropoiesis. Proteomics studies constitute a nonbiased approach to investigate differences in global protein expression. Here we will examine placental plasma proteome changes related to malarial anemia pathway at the site of parasite sequestration and inflammation-the placenta. Specifically, the study will examine 1. Changes in placental plasma proteome associated with malarial anemia by using quantitative proteomics tools. 2. Characterize the secretome of placental immune cells by quantitative proteomics. 3. Confirm that malaria anemia pathway proteins are associated with malaria anemia in cohorts of Tanzanian women. Based on these hypotheses we expect, that the relative abundance of transcription factors, growth factors and immunomodulators in placental blood associated with erythropoiesis will correlate with maternal hemoglobin levels. We expect that macrophage-specific mediators that modify erythroid proliferation and development will be more abundant in placental blood samples from primigravidas. Pregnancy malaria is the best-understood malaria syndrome. The characterization of the plasma proteome in malaria-infected pregnant women will contribute to our understanding of the host-pathogen interaction in the pregnant host, and will generate information for larger studies of novel molecules involved in the pathogenesis of severe anemia in children. PUBLIC HEALTH RELEVANCE In malaria endemic areas, pregnancy malaria is a risk factor for maternal mortality due to anemia. Pregnancy malaria and maternal anemia are independent risk factors for low birth weight (LBW) deliveries that increase the risk of mortality during the neonatal period and infancy. This study will identify potential immunological and transcriptional pathways and mediators that are pivotal in the pathogenesis of malaria associated maternal anemia.