Transgenic Mice for Sensing Bioweapons

描述（由申请人提供）：快速检测武器化病原体的释放对于公共防御生物恐怖袭击至关重要。很难对突然释放进行持续监测，特别是在大面积或偏远地区。我们建议开发对生物恐怖分子病原体的存在具有遗传超敏感性的小鼠品系，并且当暴露于生物武器生物体时会表现出过敏性休克和快速死亡。总的目标是生产出对病原体有显著和快速生理反应的动物，并作为病原体释放的哨兵。本提案的目的是进行初步研究，探讨这一办法的可行性。虽然这种方法可以很容易地针对大多数病原体，但这些初步研究将使用炭疽杆菌作为生物恐怖分子的模式生物。一个（1）具体目的是产生携带抗体重链和轻链转基因的小鼠品系，所述抗体重链和轻链转基因编码对BclA蛋白特异性的IgE抗体，所述BclA蛋白是B的孢子外壁上的免疫显性表位。炭疽病这些小鼠（Ax-IgE小鼠）被设计为具有高度升高的抗炭疽IgE水平，这将导致它们对暴露于炭疽孢子具有过敏性超敏反应。剩下的目标是进一步对Ax-IgE小鼠进行遗传修饰，以增加它们对炭疽的敏感性。这将通过将Ax-IgE小鼠与缺乏抑制因子的小鼠杂交来完成，这些抑制因子已被证明可以下调过敏反应。R21的短期支持将使这些初步研究能够显示这些转基因小鼠对炭疽孢子暴露的特异性和敏感性。这将表明这种新方法对病原体监测的潜在有效性，并为未来一系列研究提供基础，以扩大和完善这项技术。

DESCRIPTION (provided by applicant): Rapid detection of the release of weaponized pathogens is critical for public defense against bioterrorist attacks. Continuous surveillance against surprise releases is difficult, particularly in large or remote areas. We propose to develop mouse strains that are genetically hypersensitive to the presence of bioterrorist pathogens and that would exhibit anaphylactic shock and rapid death when exposed to bioweapon organisms. The overall goal is to produce animals that would have dramatic and rapid physiological responses to pathogens and serve as sentinels for pathogen release. The aims of this proposal are directed toward preliminary studies to explore the feasibility of this approach. Although the approach can easily be directed toward most pathogens, these preliminary studies will use Bacillus anthracis as a model bioterrorist organism. One (1) specific aim is to produce mouse strains that carry antibody heavy and light chain transgenes encoding IgE antibodies specific for the BclA protein that is the immunodominant epitope on the exosporium of B. anthracis. These mice (Ax-IgE mice) are designed to have highly elevated anti-anthrax IgE levels that will cause them to have allergic hypersensitivity to exposure to anthrax spores. The remaining aims are to further genetically modify Ax-IgE mice to increase their sensitivity to anthrax. This will be done by crossing the Ax-IgE mice with mice that are deficient for inhibitory factors that have been shown to downregulate allergic reactions. The short-term R21 support will allow these preliminary studies to show the specificity and sensitivity of these genetically modified mice to exposure to anthrax spores. This will indicate the potential effectiveness of this new approach to pathogen surveillance and provide a basis for a series of future studies to expand and refine this technology.