Project 3

项目3

• 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
• 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

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 暴露于环境有害物质，包括自然和人为因素 众所周知，灾害会对怀孕产生负面影响，导致不良后果，如早产（PTB）。 然而，由于缺乏一个有效的方法，在接触和怀孕风险之间建立明确的联系是具有挑战性的。 毒物激活导致母胎组织中PTB的途径的机制知识。 不幸的是，目前的体外和体内毒性测试模型不足以评估危害 受试物质对妊娠结局的影响，不代表人类在子宫内的结构和功能 或者成本太高和生产量低。此外，评估暴露造成的危害， 可能含有多种危险化学品的复杂环境样品，通常在 灾难，更具挑战性。在这里，我们建议开发一种胎儿-母体（F-M）界面组织芯片- 的测试策略，用于评估环境物质对人体健康的危害。我们的中央 一种假设是，模拟复杂的多细胞F-M界面的生理学的组织芯片模型将 能够评估受暴露于复杂环境影响的机制病理生理途径 可能增加PTB风险的有害物质。这些组织芯片模型模拟了胎儿和母体 子宫组织的结构和功能，并将用于评价机制病理生理途径 在复杂的混合环境有害物质施加的F-M界面。这将是完成 通过以下三个目标。在目标1中，我们将开发一个PTB的机制模型，以响应 环境毒物使用胎膜组织芯片模型。在目标2中，我们将开发一种机制 使用胎盘组织芯片模型的PTB模型对环境毒物的响应。在目标3中， 重点是我们的新模型在灾害研究响应（DR 2）中的应用，我们将展示快速的 环境暴露对F-M稳态破坏的潜在人类健康危害的评估 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 将为使用组织芯片进行毒物对PTB影响的危害评估提供关键和及时的信息 模型，特别是与现有超级基金场地和与紧急灾害有关的有毒物质有关的模型 污染物。从主题上讲，该项目很好地融入了德克萨斯A&M大学超级基金研究 该中心的重点是解决人类健康风险的接触有害物质期间， 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。