Core--Transgenic animal facility

该提议的一个基本假设是，对电离辐射的正常细胞保护反应可以通过施用化学保护剂和缓解剂来激活和/或增强，这将通过该提议固有的综合药物发现计划来发现。与该药物发现计划紧密相关的是一个动物计划，通过该动物核心进行操作，该动物计划将提供和开发转基因和条件性敲除小鼠模型，以帮助发现和鉴定化学保护剂。还描述了在非人灵长类动物中测试有前途的化学保护剂的规定。转基因和条件性基因敲除小鼠将通过以下方式用于发现化学保护剂：（1）提供用于测试许多有希望的化学品的保护剂性质的模式生物，（2）提供发现化学保护剂的手段，所述化学保护剂由于与已知的或不确定的生物化学和信号传导途径的相互作用而保护免受电离辐射损伤。 怀疑在预防或减轻电离辐射的影响中起主要作用，和（3）通过提供确定新设计的化学保护剂和介体试剂的生理功能的手段。动物核心的具体目标是：（1）产生转基因和基因敲除小鼠品系，以了解不同化学品对小鼠的影响。 防止辐射损伤或减轻电离辐射的影响。(2)在使用转基因和基因敲除小鼠系的实验设计和执行方面提供专业知识。(3)从动物中心产生的或动物中心获得的专门遗传小鼠品系中获取组织，供项目研究者使用。(4)从突变小鼠中获得细胞系，包括ES细胞系，用于化学保护剂和缓解剂的体外测试和研究。(5)评估涉及实验动物的结果，并提出后续实验方向。

An underlying hypothesis of this proposal is that normal cellular protective responses to ionizing radiation can be activated and/or augmented through the administration of chemoprotectants and mitigators, which will be discovered through the comprehensive drug discovery program inherent to this proposal. Tightly linked to this drug discovery program is an animal program, operated through this Animal Core that will provide and develop transgenic and conditional knockout mouse models to assist in discovery and identification of chemoprotectants. Provisions for testing promising chemoprotectants in non-human primates are also described. Transgenic and conditional knockout mice will be used in the discovery of chemoprotectants by: (1) providing model organisms for testing the protectant nature of a number of promising chemicals, (2) by providing a means of discovering chemoprotectants that protect from ionizing radiation damage due to their interaction with biochemical and signaling pathways that are known or are suspected of playing a major role in preventing or mitigating the effects of ionizing radiation, and (3) by providing a means of determining the physiologic function of the newly designed chemo-protector and mediator agents. The Specific Aims of the Animal Core are: (1) Generate transgenic and knockout lines of mice to understand the effects of different chemicals in protecting against radiation injury or in mitigating the effects of ionizing radiation. (2) Provide professional expertise in the design and execution of experiments using transgenic and knockout lines of mice. (3) Procure tissues from specialized genetic mouse lines that are generated by the Animal Core or are acquired by the Animal Core for use by the investigators in the Program. (4) Derive cell lines, including ES cell lines, from mutant mice for use in the in vitro testing and study of chemical protectors and mitigators. (5) Evaluate results involving experimental animals and propose subsequent experimental direction.