The Mutant Mouse Resource and Research Center at the University of Missouri - Applied Research Section 1

应用研究第1部分--项目摘要 经过几十年的努力，清除实验室小鼠的病原体和其他亚临床微生物能够 令人困惑的研究，有一个新的认识到，小鼠完全没有任何和所有的病毒， 细菌、原生动物和真菌病原体，甚至包括最可疑的机会主义者，基本上都是 天真的抗原，因此，可能不是合适的或理想的人类疾病模型。几项研究 已经证明宠物商店和野生老鼠在质量上与标准的实验室老鼠不同 循环记忆T细胞和免疫球蛋白图谱。这种抗原经历过的免疫表型 在感染疾病、肠道炎症和其他疾病的模型中一直与保护作用有关 肿瘤的发生，这种免疫表型可以通过肠道微生物区系(GM)进行实验转移。在 然而，为了生物安全、工人安全和可重现的数据，如果抗原- 通过实验性接种，可以在实验室小鼠中诱导出经验免疫表型 合适的微生物。因此，应用研究科的长期目标是调查和 发展在实验室小鼠中可重复地诱导经历抗原的免疫表型的方法 在先前被证明对这些因素敏感的疾病模型中具有保护作用。具体的 目的是1)测试两种候选细菌对宿主免疫反应的“挑衅者”的能力，以及 在病毒控制和两个不同的GM群落的背景下，诱导效应器记忆的分化 T细胞和免疫球蛋白的产生；2)评估小鼠在这些实验中的易感性 抗原暴露组对疾病的易感性使用两种已知的常用小鼠疾病模型 根据先前宿主抗原暴露的程度不同，严重程度也不同。具体来说，微生物 待评估的药物包括肝螺杆菌、节段性丝状细菌(念珠菌 Savagella)和小鼠肝炎病毒(MHV)，待测试的模型包括非肥胖糖尿病(NOD) 小鼠和DSS诱导的结肠炎。如果用于转译生物医学研究的传统实验室小鼠 在最近的研究表明，在疾病模型中普遍更容易受到影响，它本质上扭曲了我们的能力 识别疾病的机制和治疗方法，将时间和资源浪费在没有 转化为人类，并错失了显示可能夸大毒性的“假阴性”的机会 不会出现在有抗原经验的人身上。这些方法的发展和改进 在应用研究部分提出的建议将彻底改变生物医学研究并提高 治疗学的发展和机制的发现。此外，小鼠的产生和提供 具有抗原经验的免疫表型将扩大MU提供的服务组合 与MMRRC相关的GM及其对小鼠疾病模型的影响，并增加项目收入 通过适用于广泛调查人员的新型增值服务。

Applied Research section 1 – Project Summary After decades of efforts to rid laboratory mice of pathogens and other subclinical microbes capable of confounding research, there is an emerging realization that mice completely devoid of any and all viral, bacterial, protozoal, and fungal pathogens including even the most questionable opportunists, are essentially antigen-naïve and as such, may not serve as appropriate or ideal models of human disease. Several studies have demonstrated that pet store and wild mice are qualitatively different from standard laboratory mice in terms of circulating memory T cell and immunoglobulin profiles. This antigen-experienced immunophenotype is consistently associated with a protective effect in models of infectious disease, intestinal inflammation, and tumorigenesis, and this immunophenotype can be transferred experimental via the gut microbiota (GM). In the interests of biosecurity, worker safety, and reproducible data however, it would be ideal if the antigen- experienced immunophenotype could be induced in laboratory mice via experimental inoculation with the appropriate microbes. Thus, the long-term objectives of this Applied Research section are to investigate and develop methods of reproducibly inducing an antigen-experienced immunophenotype in laboratory mice which confers a protective effect in disease models previously shown to be sensitive to these factors. The Specific Aims are to 1) test the ability of two candidate bacterial ‘provocateurs’ of host immune responses, alongside a viral control and in the context of two distinct GM communities, to induce the differentiation of effector memory T cells and immunoglobulin production, and 2) to evaluate the susceptibility of mice in these experimental antigen exposure groups to disease susceptibility using two commonly used mouse models of disease known to differ in severity depending on the degree of previous host antigen exposure. Specifically, the microbial agents to be evaluated include Helicobacter hepaticus, segmented filamentous bacteria (Candidatus Savagella), and Murine Hepatitis Virus (MHV), and the models to be tested include Non-obese Diabetic (NOD) mice and DSS-induced colitis. If traditional laboratory mice used in translational biomedical research are universally more susceptible in disease models as suggested by recent studies, it essentially distorts our ability to identify mechanisms and therapies of disease, wasting time and resources on ‘false positives’ that do not translate to humans, and missing opportunities on ‘false negatives’ that show exaggerated toxicities that might not be present in antigen-experienced individuals. The development and refinement of methods such as those proposed in this Applied Research section will revolutionize biomedical research and increase efficiencies in the development of therapeutics and discovery of mechanisms. Moreover, generation and provision of mice with an antigen-experienced immunophenotype will expand the portfolio of services offered by the MU MMRRC related to the GM and its influence on mouse models of disease, and increase program income through novel value-added services applicable to a broad base of investigators.