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

密苏里大学突变小鼠资源和研究中心(MUMMRRC)的首要目标是向用户提供精致的小鼠模型，以便生物医学中的广泛学科 研究可以高效地推进，并具有最佳的可译性。要做到这一点，需要不断地评估 可以调节模型表型的因素以及控制甚至利用这种表型的手段的发展 调节因素。在过去的十年里，关于这样一个角色的研究呈爆炸式增长 肠道微生物区系(GM)在调节小鼠疾病模型中的作用。我们和其他人已经证明了 多种因素可以影响通用汽车的组成，更重要的是，通用汽车的变化可以改变 模型表型。考虑到这一点，MU MMRRC寻求开发方法来提供不同类型的模型 具有最佳可译性的复杂通用汽车。为此，我们创造了一大群老鼠，这些老鼠 不同的、稳定的、特征良好的复杂GM，代表了当代GM的光谱 啮齿动物聚居地。然而，有必要进行更多的研究来完善复杂的GM相关实验 设计策略。最值得注意的是，需要纳入转基因的其他组成部分，如病毒 感染使我们实验室小鼠的转基因更好地复制了人类的情况。在这项提案中，我们将 将这一概念应用于SARS-CoV-2感染研究的主要模型的精炼和优化 B6.Cg-TG(K18-ACE2)2PrlMN/J小鼠。我们将评估如何通过增加小鼠的抗原暴露 用选定的病毒和细菌制剂补充标准化的复杂转基因材料将调节 这个模型的表型。产生的结果将是无价的、立即可用的和持续的 对毁灭性的新冠肺炎大流行和培育的小鼠的研究将立即提供给 生物医学研究社区。此外，这一策略可以很容易地应用于任何额外的模型 近期出现的SARS-CoV-2感染。

An overarching goal of the Mutant Mouse Resource and Research Center at the University of Missouri (MUMMRRC) is to provide refined mouse models to its users so that the broad range of disciplines in biomedical research can advance efficiently and with optimal translatability. To do so requires constant assessment of factors that can modulate model phenotypes and development of means to control and even exploit such modulating factors. In the past decade, there has been an explosion of research on the role of one such factor, the gut microbiota (GM), in modulating murine models of disease. We and others have shown that multiple factors can influence the composition of GM and more importantly, that changes in the GM can alter model phenotypes. With this in mind, the MU MMRRC seeks to develop means to provide models on differing complex GM that have optimal translatability. To this end, we have created colonies of mice that harbor differing stable and well-characterized complex GM that represent the spectrum of GM seen in contemporary rodent colonies. However, additional research is necessary to refine complex GM-associated experimental design strategies. Most notably, there is need to incorporate other components of the GM such as viral infections so that the GM of our laboratory mice better replicate the human condition. In this proposal, we will apply this concept to refinement and optimization of a major model for the study of SARS-CoV-2 infection, the B6.Cg-Tg(K18-ACE2)2Prlmn/J mouse. We will assess how increasing antigen exposure of mice through supplementation of standardized complex GMs with selected viral and bacterial agents will modulate the phenotype of this model. Results generated will be invaluable and immediately applicable and to ongoing studies of the devastating COVID-19 pandemic and mice developed will be immediately available to the biomedical research community. Moreover, this strategy can be readily applied to any additional models for SARS-CoV-2 infection that arise in the near future.