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Incorporating Phase I/II drug/chemical metabolism in HTS via micro scale co-culture

通过微尺度共培养将 I/II 期药物/化学代谢纳入 HTS

基本信息

批准号：
10012602
负责人：
Jose Antonio Jimenez-Torres
金额：
$ 91.33万
依托单位：
ONEXIO BIOSYSTEMS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012602
关键词：
Anabolism Animal Model Animal Testing Applications Grants Area Biological Assay Biology Breast Breast Cancer Risk Factor Carcinoma Cardiac Cell Communication Cells Chemical Exposure Chemicals Coculture Techniques Competence Complex Development Devices Diffusion Disease Dose Drug Targeting End Point Assay Endocrine Environment Equipment Estrogens Event Exposure to Gastrointestinal tract structure Goals Hazardous Chemicals Hepatocyte Human Image Infrastructure Interview Kidney Lab-On-A-Chips Laboratories Lead Letters Liver Lung Measures Metabolic Metabolism Microscope Modeling Molecular National Institute of Environmental Health Sciences Ovary Performance Pharmaceutical Preparations Phase Poison Population Reader Reporter Reproducibility Research Research Personnel Risk Signal Transduction Small Business Innovation Research Grant Technology Testing Tissues Toxic effect Toxicity Tests Toxicology Tube Xenobiotic Metabolism base breast cancer progression cell type cytotoxicity drug candidate drug development drug discovery drug metabolism experimental study high standard high throughput screening improved in vivo innovation instrumentation liver metabolism malignant breast neoplasm nephrotoxicity novel therapeutics paracrine programs research and development response screening steroid metabolism toxicant tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY In place of animal testing, high throughput screening (HTS) is used to discover potential drugs and identify chemicals that are toxic to humans. Federal efforts to reduce toxicity testing in animal models that use HTS have found that traditional HTS tests lack critical biology, including drug/chemical metabolism and signaling between different cell types that would result in a more accurate prediction of human toxicities. Researchers in drug discovery and chemical testing lack a simple, affordable and high-throughput way to co-culture different cell-types together to improve the human relevance of their tests. Onexio Biosystems is developing an HTS testing platform that supports co-culture and multi-culture to improve human relevance in drug discovery and chemical toxicity testing applications. Known as the microDUO, this versatile platform technology supports the intercellular signaling necessary to improve human relevance, while maintaining full compatibility with standard HTS instrumentation. The microDUOs innovation lies in the integration of micro-scale diffusion channels between adjacent pairs or groups of wells (test tubes) in and HTS compatible format. In this grant proposal, we will continue and expand our Phase 1 SBIR R&D efforts to develop high-priority predictive toxicity assays in the MicroDUO. We will 1)confer metabolic competence (drug metabolism) to new cell types including GI, lung and ovary cells by coculturing these cells with liver hepatocyes 2)coculture different cell types from the breast to rebuild the molecular and cellular events that occur during breast cancer progression and test how chemicals in the environment might drive cancer progression. 3) test MicroDUO performance across multiple HTS laboratories and 4)produce a microscope compatible MicroDUO to enable improved understanding of cellular interactions and toxicities in co-culture.

项目摘要代替动物试验，高通量筛选（HTS）用于发现潜在的药物和鉴定对人类有毒的化学物质。联邦努力减少使用HTS的动物模型中的毒性试验我发现传统的HTS测试缺乏关键的生物学，包括药物/化学代谢和信号传导这将导致对人类毒性的更准确的预测。的研究人员药物发现和化学测试缺乏一种简单的，负担得起的和高通量的方式来共培养不同的细胞类型在一起，以提高其测试的人类相关性。Onexio Biosystems正在开发一种HTS 支持共培养和多文化的测试平台，以提高药物发现中的人类相关性，化学毒性测试应用。被称为microDUO，这种多功能平台技术支持细胞间信号传导是提高人类相关性所必需的，同时保持与标准的完全兼容性。高温超导仪器。microDUOs的创新在于整合了微尺度的扩散渠道在相邻的威尔斯孔（试管）对或组之间，以HTS兼容的格式。在这份申请中，我们将继续并扩大我们的第一阶段SBIR研发工作，以开发高优先级的预测毒性测定， MicroDUO。我们将1）赋予新的细胞类型，包括GI，肺，卵巢细胞，通过将这些细胞与肝细胞共培养2）共培养来自乳腺的不同细胞类型，重建乳腺癌进展过程中发生的分子和细胞事件，并测试化学物质可能会导致癌症的发展3)在多个HTS上测试MicroDUO性能实验室和4）生产显微镜兼容的MicroDUO，以提高对细胞的理解共培养中的相互作用和毒性。