Core--Transgenic animal facility

这项建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给予化学保护剂和缓释剂来激活和/或增强，这将通过这项建议所固有的全面药物发现计划来发现。与这一药物发现计划密切相关的是一个动物计划，该计划通过该动物核心进行操作，将提供和开发转基因和条件基因敲除小鼠模型，以帮助发现和鉴定化学保护剂。还描述了在非人类灵长类动物中测试有前景的化学保护剂的规定。转基因和条件性基因敲除小鼠将被用于化学保护剂的发现，方法是：(1)提供模型生物来测试一些有希望的化学物质的保护性质；(2)提供一种发现化学保护剂的方法，这些化学保护剂由于与已知的或被发现的生物化学和信号通路的相互作用而免受电离辐射损害。 被怀疑在预防或减轻电离辐射影响方面发挥主要作用，以及(3)通过提供一种确定新设计的化学保护剂和介体剂的生理功能的手段。动物核心的具体目标是：(1)建立转基因和基因敲除小鼠品系，以了解不同化学物质对小鼠的影响 保护免受辐射伤害或减轻电离辐射的影响。(2)在利用转基因和基因敲除小鼠品系设计和执行实验方面提供专业知识。(3)从专门的遗传小鼠品系中获取组织，这些组织由动物核心组织产生或由动物核心组织获得，供该计划的研究人员使用。(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释剂的体外测试和研究。(5)对实验动物的实验结果进行评估，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.