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

应用研究第一组-计划摘要 经过几十年的努力，消除实验室小鼠的病原体和其他亚临床微生物， 令人困惑的研究，有一个新兴的认识，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， 抗原未处理的，因此可能不能用作人类疾病的适当或理想模型。几项研究 已经证明，宠物店和野生小鼠在质量上不同于标准实验室小鼠， 循环记忆T细胞和免疫球蛋白谱。这种抗原经历的免疫表型 在感染性疾病、肠道炎症和 肿瘤发生，并且这种免疫表型可以通过肠道微生物群（GM）进行实验转移。在 然而，如果抗原- 通过实验性接种，可以在实验室小鼠中诱导经验免疫表型。 合适的微生物因此，本应用研究部分的长期目标是调查和 开发了在实验室小鼠中可重复地诱导抗原经历的免疫表型的方法， 在先前显示对这些因素敏感的疾病模型中赋予保护作用。具体 目的是：1）测试两种候选细菌“宿主”免疫应答的能力，以及 病毒控制和在两个不同的GM社区的背景下，诱导效应记忆的分化 T细胞和免疫球蛋白产生，以及2）评估这些实验中小鼠的易感性 使用两种常用的已知疾病的小鼠模型， 根据先前宿主抗原暴露的程度，严重程度不同。具体来说，微生物 待评价的药剂包括肝螺杆菌、分节丝状细菌（嗜热链球菌 Savagella）和鼠肝炎病毒（MHV），并且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。如果用于转化生物医学研究的传统实验室小鼠 正如最近的研究所表明的那样，它在疾病模型中普遍更容易受到影响，它基本上扭曲了我们的能力 确定疾病的机制和治疗方法，浪费时间和资源在“假阳性”上， 转化为人类，并错过了“假阴性”的机会，这些假阴性显示出夸大的毒性， 不存在于有抗原经历的个体中。方法的发展和完善， 在这个应用研究部分提出的将彻底改变生物医学研究和提高效率， 治疗方法的发展和机制的发现。此外，小鼠的产生和提供 与抗原经验丰富的免疫表型将扩大由MU提供的服务组合 MMRRC涉及GM及其对小鼠疾病模型的影响，并增加项目收入 通过适用于广大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.