Pathways of Maternal Anemia

描述（由申请人提供）：孕期疟疾是热带国家一个严重的公共卫生问题，它与母亲和孩子的疾病和死亡率有关。疟疾在初产妇（患此病的妇女）中引起炎症反应。胎盘中高水平的TNF-1与初生妊娠的母体贫血有关，但与多胎妊娠无关。我们假设原孕妇女的促炎信号通路改变胎盘中红细胞特异性因子的表达，通过以下一种或两种途径导致贫血。1. 炎症因子和其他巨噬细胞介质抑制胎盘因子的表达，调控红细胞生成。2. 寄生虫附着于胎盘合体滋养细胞直接调节胎盘中调节红细胞生成的因子的表达。蛋白质组学研究是研究全球蛋白质表达差异的一种无偏倚方法。在这里，我们将检查与疟原虫隔离和炎症部位-胎盘的疟疾贫血途径相关的胎盘血浆蛋白质组变化。具体来说，该研究将检查1。利用定量蛋白质组学工具研究与疟疾贫血相关的胎盘血浆蛋白质组的变化。2. 定量蛋白质组学表征胎盘免疫细胞分泌组。3. 确认疟疾贫血途径蛋白与坦桑尼亚妇女群体中的疟疾贫血相关。基于这些假设，我们预计与红细胞生成相关的胎盘血液中转录因子、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。我们预计巨噬细胞特异性调节红细胞增殖和发育的介质将在原迁鼠胎盘血液样本中更加丰富。妊娠期疟疾是人们最了解的疟疾综合症。疟疾感染孕妇血浆蛋白质组的特征将有助于我们了解妊娠宿主的宿主-病原体相互作用，并将为儿童严重贫血发病机制中涉及的新分子的更大规模研究提供信息。在疟疾流行地区，妊娠期疟疾是孕产妇患病的一个危险因素

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.