Pathways of Maternal Anemia

母亲贫血的途径

• 批准号: 8011326
• 负责人: ANDREW V OLEINIKOV
• 金额: $ 57.68万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-18 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011326
• 关键词: Address; Adhesions; Anemia; Antibodies; Area; Biological Markers; Blood; Blood specimen; Cells; Child; Chronic; Country; Development; Disease; Erythroid; Erythropoiesis; Event; Growth Factor; Health; Hemoglobin; Hemoglobin concentration result; Immune; Immune Plasma; Immunomodulators; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Interferons; Lead; Low Birth Weight Infant; Malaria; Maternal Mortality; Mediator of activation protein; Mothers; Neonatal; Outcome; Parasites; Pathogenesis; Pathway interactions; Peripheral; Pilot Projects; Placenta; Plasma; Plasmodium falciparum; Population; Pregnancy; Pregnancy Outcome; Pregnant Women; Proteins; Proteome; Proteomics; Public Health; Relative (related person); Research; Resistance; Risk; Risk Factors; Role; Sampling; Signal Pathway; Site; Syncytiotrophoblast; Syndrome; TNF gene; Time; Woman; base; cohort; cytokine; infancy; macrophage; mortality; neonatal death; novel; pathogen; pregnant; protein expression; response; tool; transcription factor

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.

描述（由申请人提供）：妊娠期疟疾是热带国家一个压倒性的公共卫生问题，与母亲和孩子的疾病和死亡有关。疟疾会引起初产妇（患有这种疾病）的炎症反应。胎盘中高 TNF-1 水平与初产妇贫血相关，但与多产妇贫血无关。我们假设初产妇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，通过以下一种或两种途径导致贫血。 1.炎症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. 寄生虫对胎盘合体滋养层的粘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研究整体蛋白质表达差异的无偏见方法。在这里，我们将在寄生虫隔离和炎症部位（胎盘）检查与疟疾贫血途径相关的胎盘血浆蛋白质组变化。具体来说，该研究将通过使用定量蛋白质组学工具来检查： 1. 与疟疾性贫血相关的胎盘血浆蛋白质组的变化。 2. 通过定量蛋白质组学表征胎盘免疫细胞的分泌组。 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，我们预计胎盘血液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。我们预计初产妇胎盘血样中调节红细胞增殖和发育的巨噬细胞特异性介质会更加丰富。妊娠期疟疾是最了解的疟疾综合征。感染疟疾的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，并将为涉及儿童严重贫血发病机制的新分子的更大规模研究提供信息。公共卫生相关性 在疟疾流行地区，妊娠期疟疾是孕产妇感染的危险因素 因贫血而死亡。妊娠期疟疾和孕产妇贫血是低出生体重（LBW）分娩的独立危险因素，会增加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学和转录途径以及在疟疾相关孕产妇贫血发病机制中至关重要的介质。