Project 4

项目4

• 批准号: 10349754
• 负责人: Ivan Rusyn
• 金额: $ 20.3万
• 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/10349754
• 关键词: Address; Analytical Chemistry; Arts; Biological; Biological Availability; Biological Models; Biomedical Engineering; Cardiac Myocytes; Case Study; Cell Line; Cells; Chemicals; 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; Metabolism; Methodology; Methods; Modeling; Molecular; Mus; Optimum Populations; Outcome; 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; base; 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 项目4旨在开发一种用于评价组织间和组织间 个体对复杂环境暴露的反应差异。这一目标是整个 德克萨斯A&M大学超级基金研究中心描述和管理人类健康的战略 与接触环境紧急情况动员的危险物质有关的风险， 开发可供第一反应者、受影响社区和政府使用的工具 参与现场管理和清理的机构。在过去的一段时间里，我们不仅开发了一个多- 用于高含量/高通量中复杂环境暴露的组织“生物交叉读取”方法 使用人诱导多能干细胞（iPSC）的测定，但也证明了其定量测定的实用性。 通过若干案例研究估计复杂环境接触的危害， 社区、国家和国际范围。这些研究表明，新的方法（NAMs） 可用于评估现实生活中暴露的风险。我们的核心假设仍然是， 基于风险的安全性评价策略，使用人体器官型体外培养物，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造成的风险， 环境紧急情况下的危险物质。首先，我们将开发一个以人口为基础的人类， 表征组织间和个体间对复杂环境响应的变异性的体外方法 暴露。我们将检验基于人群的体外模型可以改进危险预测的假设 并表征组织间和个体间变异性的分子基础和程度。第二、 我们将开发一种高通量反向毒理学（RTK）建模方法，用于复杂的暴露， 能够对环境样品进行体外到体内外推（IVIVE）。因为IVIVE对于 在人类健康的背景下，体外NAMs数据的解释，我们假设，新的药物组学 分析和新的器官芯片模型可以提供浓度依赖性和组合依赖性RTK IVIVE所需的参数，最终能够更准确地预测体内效应。第三，作为艺术 中心的灾难研究响应（DR 2）的方法，我们将展示人类的应用多， 组织和人群范围的高通量体外模型，以灾害研究反应。我们将展示 在过去的资助期内开发的“生物交叉阅读”方法可应用于DR 2，方法是测试 假设体外毒性数据可用于定量预测和表征 环境样品。我们将与所有项目合作，使用他们的样品或合作进行分析， 分子和生物医学工程方法和技术。我们将与所有核心进行数据分析 和管理，地理空间分析，并将我们的研究成果转化为受影响的社区和其他 持份者该项目的数据和方法对于应对灾害至关重要。