Project 4

项目4

基本信息

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
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/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

项目摘要

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旨在制定体内转化到体内测试策略，以评估组织间和间对复杂环境暴露的反应的个人变异性。这个目标是整体的关键部分德克萨斯A＆M大学超级基金研究中心的战略来表征和管理人类健康与通过环境紧急杀害危险物质暴露有关的风险开发急救人员，受影响社区和政府可以使用的工具现场管理和清理涉及的尸体。在过去的资金期间，我们不仅开发了组织“生物学读取”方法，用于在高含量/高通量中进行复杂的环境暴露使用人类诱导多能干细胞（IPSC）的测定，但也证明了其定量的实用性估计复杂环境暴露的危害，通过跨越的许多案例研究社区，国家和国际规模。这些研究表明了新方法方法如何（NAM）可以用于评估现实生活中的风险。我们的中心假设仍然是一个分层基于风险的安全评估策略，利用人类器官型在体外培养物中，并结合种群基于基于的反向毒性，可用于准确表征通过合并接触的风险环境紧急情况下的危险物质。首先，我们将在体外方法来表征对复杂环境的反应中的组织间和个体间的变化暴露。我们将检验以下假设，即基于人群的体外模型可以完善危害预测并表征分子基础以及组织间和个体间变异的程度。第二，我们将开发一种高通量反向TexCokinetics（RTK）建模方法，用于复杂暴露于实现环境样品的体外体内外推（IVIVE）。因为ivive对在人类健康的背景下对体外NAM数据的解释，我们假设这种新型的外展示分析和新的An-A-Chip模型可以提供浓度 - 依赖暴露的RTK ivive所需的参数，最终使体内效应的更准确预测。第三，作为艺术中心的灾难研究反应（DR2）方法，我们将证明人类多的应用组织和人口范围内的高通量体外模型，以灾难研究反应。我们将展示如何在过去的资金期间开发的“生物读取方法”可以通过测试来应用于DR2 假设体外毒性数据可用于定量预测和表征健康危害环境样品。我们将与所有项目合作，以使用其样本或合作进行分析，分子和生物医学工程方法和技术。我们将与所有核心合作进行数据分析以及管理，地理空间分析以及我们的研究向受影响社区和其他利益相关者。该项目的数据和方法在对灾难的反应中至关重要。