Rapid Screen for Genotoxicants, Chemoprotectors, and Radioprotectors

快速筛查基因毒物、化学保护剂和放射保护剂

• 批准号: 7404983
• 负责人: STEPHEN D DERTINGER
• 金额: $ 57.76万
• 依托单位: LITRON LABORATORIES, LTD.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404983
• 关键词: Address; Aneugens; Automation; Biological Assay; Biological Response Modifiers; Businesses; Cancer Patient; Cell Line; Cells; Characteristics; Chemical Industry; Chemicals; Chemistry; Chromosomes; Collaborations; Compatible; DNA Damage; Data; Development; Devices; Drug Industry; End Point; Evaluation; Flow Cytometry; Hepatocyte; Human; Human Cell Line; In Vitro; Industry; Investigation; Laboratories; Lead; Libraries; Liquid substance; Malignant Neoplasms; Measurement; Measures; Medical center; Medicine; Metabolic Activation; Methodology; Methods; Micronucleus Tests; Military Personnel; Miniaturization; Molecular Biology; Mutagenicity Tests; Numbers; Operative Surgical Procedures; Other Resources; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Poison; Protocols documentation; Purpose; Radiation Oncology; Radio; Range; Reagent; Reproducibility; Research Personnel; Research Project Grants; Resources; Robotics; Safety; Sales; Scientist; Score; Screening procedure; Sensitivity and Specificity; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Staging; System; TP53 gene; Technology; Testing; Therapeutic; Time; Toxic effect; Universities; Upper arm; Validation; War; Work; assay development; base; clastogen; cytotoxicity; design; genotoxicity; instrumentation; micronucleus; miniaturize; next generation; portability; programs; protocol development; radiation effect; research study; tool

DESCRIPTION (provided by applicant): This research project addresses an important problem faced by the chemical and drug industries-their requirement to evaluate the DNA damaging potential of ever increasing numbers of new chemical entities in shorter periods of time. This situation presents opportunities for small businesses that are able to provide solutions to these challenges. Our proposal answers industry's need for higher throughput toxicity assessment through the development of an automated in vitro chromosomal damage assay. Chromosome damage will be quantified by flow cytometric micronucleus measurements. Importantly, the methodology that will be developed over the course of this project not only represents a high volume genotoxicant screening system, but also one that can be configured to identify agents which protect against chromosomal damage, i.e. biological response modifiers (BRMs). BRMs provide chemo- or radio-protection benefits that hold great promise in several important arenas, including treatment of cancer patients, protection of our troops during times of war, and for treatment of civilian victims of chemical or radiological terrorist attacks. The proposed Phase II experiments will initially focus on developing the methodologies that will allow us to incorporate automatic liquid handling devices into a miniaturized assay. By eliminating transfer steps and other labor-intensive tasks, the assay will meet the specifications of pharmaceutical and chemical companies that have high volume testing requirements. Once this is established, we, and our collaborators in the pharmaceutical industry, will evaluate a panel of genotoxicants and non-genotoxicants, thereby providing information regarding assay portability, sensitivity, and specificity. Additionally, two other lines of investigation will be undertaken: evaluation of the HepG2 liver cell line; and utilization of the micronucleus scoring assay for the purposes of radioprotectant identification/characterization. Ultimately, optimization and validation of this screening assay will help chemical and drug companies allocate their resources to their most promising candidates, eliminating hazardous entities early in development. Furthermore, by aiding in the identification of next generation BRMs, cancer patients and armed forces will benefit from the availability of chemo- and radio-protectant drugs. Along with recent advancements in the fields of molecular biology, chemistry and medicine comes an ever- increasing number of new and potentially helpful drugs and industrial chemicals. The ability of pharmaceutical and chemical companies to prioritize these agents in terms of safety and efficacy is often hampered by the use of outdated methods and/or technologies. This proposal addresses the stated need for an automated and miniaturized in vitro micronucleus assay designed to rapidly and efficiently detect the chromosome damaging potential of drugs and chemicals. In addition, this assay can be used to investigate agents designed to ameliorate the effects of radiation exposure, e.g. biological response modifiers.

描述（由申请人提供）：本研究项目解决了化学和药物工业面临的一个重要问题——他们需要在更短的时间内评估越来越多的新化学实体的DNA损伤潜力。这种情况为能够为这些挑战提供解决方案的小型企业提供了机会。我们的建议通过开发一种自动化的体外染色体损伤分析来满足行业对高通量毒性评估的需求。染色体损伤将通过流式细胞仪微核测量来量化。重要的是，将在本项目过程中开发的方法不仅代表了一个大容量的基因毒物筛选系统，而且还可以配置为识别防止染色体损伤的药物，即生物反应调节剂（BRMs）。brm提供化学或放射性防护，在几个重要领域具有巨大的前景，包括治疗癌症患者、在战争期间保护我们的部队，以及治疗化学或放射性恐怖袭击的平民受害者。拟议的II期实验最初将侧重于开发方法，使我们能够将自动液体处理设备纳入小型分析。通过消除转移步骤和其他劳动密集型任务，该分析将满足具有高容量测试要求的制药和化学公司的规格。一旦确定，我们和我们在制药行业的合作者将评估一组基因毒物和非基因毒物，从而提供有关分析可移植性、敏感性和特异性的信息。此外，还将开展另外两项研究：HepG2肝细胞系的评估；微核评分法在放射性保护剂鉴定/表征中的应用。最终，这种筛选试验的优化和验证将帮助化学和药物公司将资源分配给最有希望的候选药物，在开发早期消除危险实体。此外，通过帮助识别下一代brm，癌症患者和武装部队将受益于化学和放射保护药物的可用性。随着分子生物学、化学和医学领域的最新进展，出现了越来越多的新型和潜在有用的药物和工业化学品。由于使用过时的方法和/或技术，制药和化学公司在安全性和有效性方面优先考虑这些药剂的能力往往受到阻碍。本提案解决了对自动化和小型化体外微核测定的既定需求，旨在快速有效地检测药物和化学品的染色体损伤潜力。此外，该试验可用于研究旨在改善辐射暴露影响的药剂，例如生物反应调节剂。