Project 3

项目3

基本信息

批准号：
10707445
负责人：
Arum Han
金额：
$ 21.1万
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/10707445
关键词：
37 weeks gestation Address Affect Aging Animal Model Cells Chemicals Child Clinical Clinical Research Coculture Techniques Collaborations Complex Complex Mixtures Data Data Analyses Decidua Basalis Disasters Emergency Situation Environmental Exposure Environmental Hazards Environmental Impact Environmental Monitoring Environmental Pollutants 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 Link Measures Membrane Methods Modeling Neonatal Mortality Oxidative Stress Pathway interactions Physiology Placenta Pregnancy Pregnancy Outcome Pregnant Women Premature Birth Research Risk Risk Assessment Risk Reduction Sampling Science Side Structure Superfund System Technology Testing Texas Tissue Microarray Tissues Toxic Environmental Substances Toxic effect Toxicity Tests Toxicokinetics Toxicology Universities Uterus Vulnerable Populations Work adverse outcome adverse pregnancy outcome anthropogenesis cost data management decidua parietalis detection method fetal improved in utero in vitro Model in vivo neonatal morbidity novel potential biomarker premature remediation 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摘要暴露于环境危险物质，包括天然和人为的物质已知灾难会对怀孕产生负面影响，导致不良后果，例如早产（PTB）。但是，由于缺乏有毒物质激活途径引起PTB的机理知识。不幸的是，当前的体外和体内毒性测试模型要么不足以评估危害在妊娠结局上测试的物质，在子宫结构和功能中不代表人此外，对暴露施加的危害的评估对于可能包含多种危险化学物质的复杂环境样品，经常在灾难，甚至是更大的挑战。在这里，我们建议开发feto-tretnal（f-M）界面组织芯片基于评估PTB环境物质的人类健康危害的基于测试策略。我们的中心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启用评估受暴露于复杂环境影响的机械病理生理途径可能增加PTB风险的危险物质。这些组织芯片模型模仿胎儿和母体子宫组织在结构和功能上，并将用于评估机械病理生理途径在复杂的混合环境危险物质施加的F-M界面中。这将完成通过以下三个目标。在AIM 1中，我们将开发PTB的机械模型使用胎儿膜组织芯片模型的环境有毒物质。在AIM 2中，我们将开发机械 PTB的模型使用Plopeta组织芯片模型响应环境有毒物质。在AIM 3中，它将专注于我们新颖的灾难研究响应模型（DR2）的应用，我们将证明快速评估潜在的人类健康危害环境暴露于破坏F-M稳态的危害通过使用高通量F-M组织芯片模型，这可能会导致PTB。这项拟议研究的成功将提供有关使用组织芯片对PTB影响的危害评估的关键和及时信息模型，尤其是与现有超级基金网站的毒物和紧急灾难有关的模型污染物。从主题上讲，该项目已很好地整合到德克萨斯农工大学超级基金研究中重点是解决人类健康在和危险物质中的风险紧急情况之后，尤其是对特别脆弱人群（孕妇和儿童）的影响。