Project 4

项目4

• 批准号: 10707452
• 负责人: Ivan Rusyn
• 金额: $ 20.42万
• 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/10707452
• 关键词: Address; Analytical Chemistry; Biological; Biological Availability; Biological Models; Biomedical Engineering; Cardiac Myocytes; Case Study; Cell Line; Cells; Chemicals; Collaborations; Communities; Complex; Computer Models; Consumption; Data; Data Analyses; Disasters; Dose; Emergency Situation; Environmental Exposure; Environmental Hazards; Environmental Monitoring; Equipment; Ethnic Origin; Evaluation; Event; Exposure to; Funding; Future; Genome; Goals; Government; Hazardous Substances; Health; Health Hazards; Human; Image; In Vitro; Individual; International; Knowledge; Life; Maps; Metabolism; Methodology; Methods; Modeling; Molecular; Mus; Outcome; Parameter Estimation; Persons; Physiological; Population; Population Sizes; Race; Renal clearance function; Reproducibility; Research; Resources; Risk; Risk Assessment; Safety; Sampling; Science; Site; Source; Specificity; Study models; Superfund; System; Techniques; Testing; Texas; Time; Tissue Microarray; Tissues; Toxic effect; Toxicokinetics; Translational Research; Translations; Universities; Work; community engagement; data management; design; detection method; evidence base; experimental study; first responder; hazard; health assessment; high dimensionality; high throughput screening; human model; in vitro Model; in vivo; in vivo evaluation; induced pluripotent stem cell; inter-individual variation; liver metabolism; lymphoblast; man-made disasters; novel; novel strategies; organ on a chip; population based; response; sex; superfund site; tool; tool development

Project 4 ABSTRACT Project 4 aims to develop a translational in vitro-to-in vivo testing strategy for evaluating the inter-tissue and inter- individual variability in responses to complex environmental exposures. This goal is a critical part of the overall strategy of the Texas A&M University Superfund Research Center to characterize and manage the human health risks associated with exposure to environmental emergency-mobilized hazardous substances through the development of tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup. In the past funding period, we not only developed a multi- tissue “biological read-across” approach for complex environmental exposures in high-content/high-throughput assays using human induced pluripotent stem cells (iPSC), but also demonstrated its utility for quantitative estimation of hazard of complex environmental exposures through a number of case studies that spanned community, national and international scales. These studies show how new approach methodologies (NAMs) can be applied for assessment of risks from real-life exposures. Our central hypothesis remains that a tiered risk-based strategy for safety evaluation utilizing human organotypic in vitro cultures, combined with population- based reverse toxicokinetics, can be used to accurately characterize the risks posed by combined exposures to hazardous substances during environmental emergencies. First, we will develop a population-based human in vitro approach to characterize inter-tissue and inter-individual variability in responses to complex environmental exposures. We will test the hypothesis that human population-based in vitro models can refine hazard predictions and characterize the molecular underpinnings and extent of inter-tissue and inter-individual variability. Second, we will develop a high-throughput reverse toxicokinetics (RTK) modeling approach for complex exposures to enable in vitro-to-in vivo extrapolation (IVIVE) of environmental samples. Because IVIVE is critical for interpretation of in vitro NAMs data in the context of human health, we hypothesize that novel exposomic analyses and new organ-on-a-chip models can provide concentration- and combined exposure-dependent RTK parameters needed for IVIVE, ultimately enabling more accurate predictions of effects in vivo. Third, as art of Center’s Disaster Research Response (DR2) approach, we will demonstrate the application of human multi- tissue and population-wide high-throughput in vitro models to disaster research response. We will show how the “biological read-across” method developed in the past funding period can be applied to DR2 by testing the hypothesis that in vitro toxicity data can be used to quantitatively predict and characterize health hazard of environmental samples. We will partner with all Projects to use their samples or collaborate on analytical, molecular and biomedical engineering methods and techniques. We will work with all Cores for data analysis and management, geospatial analysis, and translation of our research to the impacted communities and other stakeholders. The data and methods from this project will be of critical importance in responses to disasters.

项目 4 摘要 项目 4 旨在开发一种体外到体内的转化测试策略，用于评估组织间和细胞间的相互作用。 对复杂环境暴露的反应存在个体差异。这一目标是总体目标的关键部分。 德克萨斯农工大学超级基金研究中心描述和管理人类健康的战略 与暴露于环境紧急情况下动员的危险物质相关的风险 开发可供急救人员、受影响社区和政府使用的工具 在过去的资助期间，我们不仅开发了多个参与现场管理和清理的机构。 针对高内涵/高通量复杂环境暴露的组织“生物跨读”方法 使用人类诱导多能干细胞（iPSC）进行测定，但也证明了其在定量方面的实用性 通过多个案例研究评估复杂环境暴露的危害 这些研究展示了新方法论 (NAM) 的作用。 我们的中心假设仍然是分层的。 基于风险的安全评估策略，利用人体器官体外培养物，结合人群 基于反向毒代动力学，可用于准确描述组合暴露所带来的风险 首先，我们将培养以人口为基础的人类。 体外方法来表征组织间和个体间对复杂环境反应的变异性 我们将检验基于人群的体外模型可以完善危险预测的假设。 并描述组织间和个体间变异的分子基础和程度。 我们将开发一种高通量逆毒代动力学 (RTK) 建模方法，用于复杂的暴露 实现环境样本的体外到体内外推 (IVIVE)，因为 IVIVE 对于环境样本至关重要。 在人类健康背景下解释体外 NAM 数据时，我们追求这种新颖的暴露体 分析和新的器官芯片模型可以提供浓度和组合暴露依赖性 RTK IVIVE 所需的参数，最终能够更准确地预测体内效果。 中心的灾难研究响应（DR2）方法，我们将展示人类多方面的应用 我们将展示如何建立组织和人群高通量体外模型来应对灾难。 过去资助期间开发的“生物读取”方法可以通过测试 假设体外毒性数据可用于定量预测和表征健康危害 我们将与所有项目合作使用他们的样品或进行分析、 我们将与所有核心人员合作进行数据分析。 和管理、地理空间分析以及将我们的研究成果转化为受影响的社区和其他人 该项目的数据和方法对于应对灾害至关重要。