A PROTYPE NEUROTOXICOLOGICAL DATABASE

化学化合物的毒性评估在其商业开发中往往是关键和限速的组成部分。目前建立的监管环境要求，提供所需安全裕度所需的大多数（如果不是全部）毒性试验必须在动物模型中完成，如果是药品，则必须在人体临床试验中完成。目前有必要开发和验证可信的体外毒性终点，其与化合物在人体中的已知作用相似。该NIH SBIR第一阶段资助申请的目标是为经过验证的体外毒性数据库提供一个初步框架，该数据库可供制药，化学，农业和生物技术行业使用。一旦完成，该数据库将用于帮助评估新化学制剂的安全特性，这些新化学制剂可能作为治疗药物施用于人类或动物，或通过其使用对人群构成显著暴露潜力。具体而言，我们将：i）定义和验证永生化细胞系用于检测和平行体内毒性模式的用途，ii）在预测体外神经毒性中评估神经元毒性的几个体外终点，iii）建立药物和化合物体外毒性的初始数据库，（iv）启动分析工具的开发，以挖掘体外数据库，在体内研究之前提供关于新化学实体的预测毒性信息试验.拟议的商业应用：这项研究将提供一个初步的数据集和体外毒理学终点的验证，可用于制药，化工和农业行业在商业化合物的开发。它将加速新活性剂的开发，并将在化合物开发的早期阶段部分消除体内毒理学的昂贵和有问题的问题。该数据集将合并到NovaScreen目前正在构建的更大内容数据库中，其中包括全面的受体和酶数据以及广泛的化学和药理学信息。

The assessment of the toxicity of chemical compounds is an often critical and rate limiting component in their commercial development. The currently established regulatory environment demands that most if not all toxicity testing needed to provide required margins of safety be completed in animal models and, in the case of pharmaceuticals, in human clinical trials. There is currently a need to develop and validate credible in vitro toxicity endpoints that parallel the known effects of compounds in humans. The goal of this NIH SBIR Phase I Grant Application is to provide an initial framework for a validated in vitro toxicity database that can be utilized by the pharmaceutical, chemical, agricultural and biotechnology industries. Once complete, this database will be employed to aid in evaluating the safety characteristics of new chemical agents that may be administered to humans or animals as therapeutics or that pose significant exposure potential to human populations through their use. Specifically, we will : i) define and validate the use of immortalized cell lines to detect and parallel in vivo toxicity patterns, ii) evaluate several in vitro endpoints of neuronal toxicity in predicting in vitro neurotoxicity, iii) establish an initial data- base of in vitro toxicity of drugs and chemical compounds, and iv) initiate development of analytical tools to mine the in vitro database to provide predictive toxicity information about new chemical entities prior to in vivo testing. PROPOSED COMMERCIAL APPLICATIONS: This research will provide an initial dataset and validation of in vitro toxicology endpoints that can be employed by the pharmaceutical, chemical and agricultural industries in the development of commercial compounds. It will speed the development of new active agents and will in part remove the expensive and problematic issues of in vivo toxicology at an early stage in compound development. This dataset will be merged into a larger content database currently being constructed by NovaScreen that includes comprehensive receptor and enzyme data as well as extensive chemical and pharmacological information.