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Functional Read-Out Enabling High Compound Throughput Toxicokinetic Assays

功能读出可实现高化合物通量毒代动力学测定

基本信息

批准号：
10080462
负责人：
BRUCE E. SELIGMANN
金额：
$ 22.5万
依托单位：
BIOSPYDER TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-11 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080462
关键词：
Acetaminophen Address Agriculture Animal Model Animals Benchmarking Binding Biological Assay Buffers Caco-2 Cells Calibration Cells Characteristics Charge Chemical Industry Chemicals Consumption Cosmetics Data Data Analytics Development Dose Employee Environment Exposure to Gene Expression Gene Expression Profile Gene Expression Profiling Genes Haloperidol Health Hepatocyte Human Human Resources In Vitro Incubated Individual Industrialization Literature Measurement Measures Metabolic Methods Modeling Molecular Outcome Pathway interactions Permeability Petroleum Phase Plasma Process Propylthiouracil Protocols documentation Publishing Recovery Rifampin Risk Risk Assessment Safety Series System Tamoxifen Testing Time Toxic effect Toxicokinetics analytical method base comparative data standards design differential expression follow-up genetic signature improved in vitro testing in vivo in vivo evaluation innovation programs response success transcriptome

项目摘要

Summary: This Phase I project will implement and demonstrate the feasibility and utility of a new “universal” assay readout to provide high throughput in vitro toxicokinetics (HTTK) data without having to develop specific analytical methods to measure each compound. The amount of available compound from standard in vitro toxicokinetic modes of plasma binding, metabolic clearance, and bidirectional permeability will be quantified using the microplate-based TempO-Seq® gene expression platform, the S1500+v2 surrogate whole transcriptome assay which measures every known molecular pathway, and a HepaRG cell system to first identify a gene expression signature that is characteristic of each test compound and generate dose response data, then use this and benchmark concentration (BMC) analysis of signature genes and pathways as a calibration curve to quantify the amount of compound available from each in vitro toxicokinetic model. The in vitro TempO-Seq HTTK data will also identify potential safety issues and provide data useful for read-across comparisons, making the assay highly efficient by providing both the in vitro safety and in vitro toxicokinetic data necessary to make in vitro-to-in vivo extrapolations (IVIVE) and prioritize compounds for follow-up based on exposure safety risk. Reference compounds will be tested and we will benchmark the TempO-Seq HTTK data against published data obtained using analytical methods, and also demonstrate that TempO-Seq HTTK results are equivalent to IVIVE results determined using analytical methods. Unlike a functional assay using a single endpoint specific for the compound being measured, the TempO-Seq S1500v2 assay has been shown by numerous labs to provide a signature of many robustly differentially expressed genes for all compounds tested to-date, unique for each compound. Thus, this content represents a “universal” assay for any test compound or mixture (e.g. as produced in industrial chemical processes), producing compound specific signatures for use in the TempO-Seq HTTK assay. By enabling the high throughput in vitro assessment of toxicokinetics of thousands of compounds, the TempO-Seq HTTK assay will enable programs such as ToxCast to achieve the objective of providing IVIVE assessment of the tens of thousands of compounds humans and the environment are exposed to for which there are no safety data. It will also provide the pharma, agricultural, cosmetics, and petroleum/chemical industries comparative in vitro toxicity and toxicokinetic data supporting IVIVE analysis to assist synthetic chemists in design and development decisions for advancing chemical series and leads or protection of employees from exposure, and has the potential to spare animals by preselecting the compounds put into animal models.

摘要：这个第一期项目将实施并展示一种新的“通用”的可行性和实用性。