Exploring the etiology of oxidative damage and cell death in placental malaria

探索胎盘疟疾氧化损伤和细胞死亡的病因

基本信息

批准号：
10586386
负责人：
JULIE M MOORE
金额：
$ 41.2万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586386
关键词：
Ablation Address Affect Antioxidants Antiphospholipid Syndrome Automobile Driving Biology Birth Birth Weight Blood Cell Death Cells Cellular Stress Cessation of life Chemicals Child Chronic Coculture Techniques Data Development Disease Ensure Erythrocytes Etiology Exposure to Fetal Growth Retardation Fetal health Fetus Foundations Functional disorder Future Histologic Human Immune In Vitro Infant Infection Infiltration Inflammation Inflammatory Inflammatory Response International Intervention Invaded Knowledge Lead Link Lipid Peroxidation Malaria Mediating Mediator of activation protein Modeling Molecular Monitor Mus Necrosis Outcome Oxidative Stress Oxygen Parasites Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Peroxidases Placenta Plasmodium falciparum Play Population Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Premature Birth Prevention Production Public Health Reactive Oxygen Species Research Respiratory Burst Risk Role Sampling Source Stress Syncytiotrophoblast Testing Tissues Villous Woman Work abortion biological adaptation to stress cell injury cell type experience experimental study fetal hemozoin improved in vivo in vivo Model infant death inhibitor malaria infection monocyte mouse model neutrophil new therapeutic target oxidative damage pathogen placental malaria pregnancy disorder preservation reproductive response simulation stillbirth transcriptomics trophoblast

项目摘要

Abstract Malaria is a major public health problem for many regions of the world, affecting mainly pregnant women and young children. Plasmodium falciparum infection during pregnancy results in significant fetal compromise and contributes to hundreds of thousands of infant deaths each year. These outcomes are associated with a number of malaria-induced placental pathologies, including infiltration of maternal inflammatory cells into the placenta in response to the infection. This, in turn, is linked to significant damage to the villous placenta, including necrotic death of syncytiotrophoblast. Complete understanding of the critical cellular and molecular mechanisms that drive placental damage and dysfunction in placental malaria, however, remains elusive. Evidence suggests that neutrophils and monocytes accumulate in inflammatory placental malaria, and neutrophils in particular are also implicated in severe malaria in non-pregnant patients. However, few details of the roles of these cells in placental malaria pathogenesis are available. Motivated by exciting preliminary data that show profound lipid peroxidation in placental malaria, we hypothesize that activated innate immune cells, through oxidative mechanisms, directly contribute to syncytiotrophoblast stress and death in placental malaria, thereby precipitating poor birth outcomes via placental dysfunction. The objective of this application is to address this hypothesis using placenta tissue from a malaria endemic population, villous explants and a mouse model that recapitulates key aspects of placental malaria. The study objectives will be achieved through three Specific Aims. First, preserved placental tissues from Kenyan women exposed to malaria will be assessed by spatial transcriptomics to establish the extent to which trophoblast oxidative stress and necroptosis are coincident in natural infection. Second, the impact of trophoblast exposure to activated neutrophils and monocytes will be characterized in an in vitro simulation of placental malaria. Oxidative damage, necroptosis and other cell death mechanisms, and syncytiotrophoblast destruction will be monitored in villous explants exposed to neutrophils and monocytes undergoing respiratory burst. Third the role of neutrophil and monocyte oxidative burst, and the relative role of pro-oxidant malarial hemozoin, in driving placental oxidative stress and damage will be investigated in an outbred mouse model for placental malaria. Successful completion of this research will expand understanding of the mechanistic basis of malaria-induced placental damage and fetal compromise, leading to identification of new targets for adjunctive therapies in malaria during pregnancy. By advancing fundamental knowledge of mediators of syncytiotrophoblast compromise and death, this work will have implications for other pregnancy conditions associated with maternal monocyte and neutrophil activity, placental oxidative damage, and cell death-related placental dysfunction.

抽象的疟疾是世界许多地区的一个主要公共卫生问题，主要影响孕妇和妇女年幼的孩子。怀孕期间恶性疟原虫感染会导致胎儿严重受损，每年导致数十万婴儿死亡。这些结果与疟疾引起的胎盘病变的数量，包括母体炎症细胞浸润到胎盘胎盘对感染的反应。反过来，这与绒毛胎盘的严重损伤有关，包括合体滋养层坏死。全面了解关键的细胞和分子然而，导致胎盘疟疾胎盘损伤和功能障碍的机制仍然难以捉摸。有证据表明，中性粒细胞和单核细胞在炎性胎盘疟疾中积聚，并且尤其是中性粒细胞也与非怀孕患者的严重疟疾有关。不过，细节很少这些细胞在胎盘疟疾发病机制中的作用是已知的。受到令人兴奋的初步数据的激励在胎盘疟疾中显示出严重的脂质过氧化，我们假设激活了先天免疫细胞，通过氧化机制，直接导致胎盘疟疾中的合体滋养层应激和死亡，从而通过胎盘功能障碍导致不良的分娩结果。该应用程序的目的是使用来自疟疾流行人群的胎盘组织、绒毛外植体和小鼠来解决这一假设该模型概括了胎盘疟疾的关键方面。研究目标将通过三个具体目标来实现。首先，保存胎盘组织将通过空间转录组学对接触疟疾的肯尼亚妇女进行评估，以确定其感染程度滋养层氧化应激和坏死性凋亡在自然感染中同时发生。二、影响滋养层暴露于活化的中性粒细胞和单核细胞将在体外模拟中进行表征胎盘疟疾。氧化损伤、坏死性凋亡和其他细胞死亡机制以及合体滋养层将监测暴露于中性粒细胞和单核细胞的绒毛外植体中的破坏情况爆裂。第三，中性粒细胞和单核细胞氧化爆发的作用，以及促氧化剂疟疾的相对作用疟原虫色素在驱动胎盘氧化应激和损伤方面的作用将在远交小鼠模型中进行研究胎盘疟疾。这项研究的成功完成将扩大对机制基础的理解疟疾引起的胎盘损伤和胎儿受损，导致确定辅助治疗的新目标怀孕期间疟疾的治疗。通过提高调解员的基础知识合体滋养层受损和死亡，这项工作将对其他妊娠状况产生影响与母体单核细胞和中性粒细胞活性、胎盘氧化损伤以及细胞死亡相关胎盘功能障碍。