Project 3

项目3

基本信息

批准号：
10349753
负责人：
Arum Han
金额：
$ 22.26万
依托单位：
TEXAS A&M UNIVERSITY
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 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10349753
关键词：
37 weeks gestation Address Affect Aging Animal Model Cells Chemicals Child Clinical Research Complex Complex Mixtures Data Data Analyses Decidua Basalis Disasters Emergency Situation Environmental Exposure Environmental Hazards Environmental Impact Environmental Monitoring Environmental Pollution Epidemiology Evaluation Event Exposure to Fetal Membranes Fetal Tissues Fetus Future Hazard Assessment Hazardous Chemicals Hazardous Substances Health Health Hazards Homeostasis Human Immune Tolerance In Vitro Individual Inflammation Inflammatory Inflammatory Response Intervention Kinetics Knowledge Lead Link M cell Measures Membrane Methods Modeling Neonatal Mortality Oxidative Stress Pathway interactions Physiology Placenta Pregnancy Pregnancy Outcome Pregnant Women Premature Birth Research Risk Sampling Science Side Structure Superfund System Technology Testing Texas Time Tissue Microarray Tissues Toxic Environmental Substances Toxic effect Toxicity Tests Toxicokinetics Universities Uterus Vulnerable Populations Work adverse outcome adverse pregnancy outcome anthropogenesis base clinical toxicology cost data management decidua parietalis detection method fetal hazard improved in utero in vitro Model in vivo neonatal morbidity novel potential biomarker premature response senescence success superfund site therapeutic target tool toxicant

项目摘要

Project 3 Abstract Exposures to environmental hazardous substances, including those in the event of natural and anthropogenic disasters, are known to negatively impact pregnancy, leading to adverse outcomes such as preterm birth (PTB). However, establishing a clear link between exposure and pregnancy risk is challenging, due to lack of a mechanistic knowledge by which toxicants activate pathways causing PTB in maternal-fetal tissues. Unfortunately, current in vitro and in vivo toxicity testing models are either not sufficient in assessing the hazards of tested substances on pregnancy outcomes, do not represent the human in utero structure and functions accurately, or are too costly and low throughput. In addition, assessment of the hazards imposed by exposures to complex environmental samples that may contain multiple hazardous chemicals, often observed after disasters, is even more challenging. Here, we propose to develop a feto-maternal (F-M) interface tissue chip- based testing strategy for assessing the human health hazard of environmental substances on PTB. Our central hypothesis is that a tissue chip model that mimics the physiology of the complex multi-cellular F-M interface will enable evaluation of the mechanistic pathophysiologic pathways affected by exposure to complex environmental hazardous substances that may increase the risk of PTB. These tissue chip models mimic the fetal and maternal uterine tissues structurally and functionally, and will be used to evaluate mechanistic pathophysiologic pathways in the F-M interface imposed by complex mixed environmental hazardous substances. This will be accomplished through the following three aims. In Aim 1, we will develop a mechanistic model of PTB in response to environmental toxicants using a fetal membrane tissue chip model. In Aim 2, we will develop a mechanistic model of PTB in response to environmental toxicants using a placenta tissue chip model. In Aim 3, which will focus on the application of our novel models for Disaster Research Response (DR2), we will demonstrate rapid assessment of the potential human health hazards of environmental exposures on disrupting F-M homeostasis that can lead to PTB by using a higher-throughput F-M tissue chip model. The success of this proposed research will provide critical and timely information for hazard assessment on toxicants’ impact on PTB using tissue chip models, especially related to toxicants from existing Superfund sites and from emergency disaster-related contaminants. Thematically, this project is well integrated into the Texas A&M University Superfund Research Center that is focusing on addressing the human health risks of exposure to hazardous substances during and after emergencies, especially the effects on particularly vulnerable populations (pregnant women and children).

项目3摘要接触对环境有害的物质，包括自然和人为的物质众所周知，灾害会对怀孕产生负面影响，导致早产 (PTB) 等不良后果。然而，由于缺乏可靠的证据，在暴露与怀孕风险之间建立明确的联系具有挑战性。毒物激活母胎组织中引起 PTB 的途径的机制知识。不幸的是，当前的体外和体内毒性测试模型不足以评估危害对妊娠结局进行测试的物质并不代表人类在子宫内的结构和功能准确，或者成本太高且通量低。此外，对暴露造成的危害进行评估。对于可能含有多种危险化学品的复杂环境样本，通常在之后观察到在这里，我们建议开发一种胎儿-母体（F-M）接口组织芯片—— 基于 PTB 的环境物质对人类健康危害评估的测试策略。假设是模仿复杂多细胞 F-M 界面生理学的组织芯片模型将能够评估受复杂环境暴露影响的机械病理生理途径可能增加 PTB 风险的有害物质这些组织芯片模型模仿胎儿和母体。子宫组织的结构和功能，并将用于评估机制病理生理途径在复杂的混合环境有害物质施加的 F-M 界面中，这将得以实现。通过以下三个目标，我们将开发一个 PTB 力学模型来响应。在目标 2 中，我们将开发一种机制。在目标 3 中，使用胎盘组织芯片模型构建 PTB 响应环境毒物的模型。重点关注我们的灾难研究响应（DR2）新颖模型的应用，我们将展示快速评估环境暴露对破坏 F-M 稳态的潜在人类健康危害通过使用更高通量的 F-M 组织芯片模型可以导致 PTB 这项研究的成功。将使用组织芯片为有毒物质对 PTB 影响的危害评估提供关键而及时的信息模型，特别是与现有超级基金站点和紧急灾难相关的有毒物质有关的模型从主题上讲，该项目很好地融入了德克萨斯农工大学超级基金研究。该中心致力于解决在期间和期间接触有害物质的人类健康风险紧急情况发生后，特别是对特别弱势群体（孕妇和儿童）的影响。