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

密苏里州大学突变小鼠资源和研究中心（MUMMRRC）的首要目标是为其用户提供精细的小鼠模型，以便生物医学领域的广泛学科 研究可以有效地推进，并具有最佳的可翻译性。要做到这一点，需要不断评估 可以调节模型表型的因子以及控制甚至利用这些因子的方法的开发 调节因素。在过去的十年里，关于这种基因的作用的研究出现了爆炸式增长。 因子，肠道微生物群（GM），在调节疾病的小鼠模型。我们和其他人已经证明， 多种因素可以影响GM的组成，更重要的是，GM的变化可以改变 模型表型考虑到这一点，MU MMRRC寻求制定方法，提供不同的模型， 具有最佳可译性的复杂GM。为了达到这个目的，我们创造了老鼠的殖民地， 不同的稳定和良好的特点复杂的转基因，代表了当代看到的转基因光谱， 啮齿动物群落。然而，还需要进一步的研究来完善复杂的转基因相关实验。 设计策略最值得注意的是，需要将转基因的其他成分，如病毒， 感染，使我们的实验室小鼠的转基因更好地复制人类的条件。在本提案中，我们将 将这一概念应用于SARS-CoV-2感染研究的主要模型的改进和优化， B6.Cg-Tg（K18-ACE 2）2 Prlmn/J小鼠。我们将评估如何增加小鼠的抗原暴露， 用选定的病毒和细菌因子补充标准化的复合GM将调节 这个模型的表型。产生的结果将是非常宝贵的，立即适用，并将持续 对毁灭性的COVID-19大流行和小鼠的研究将立即提供给 生物医学研究社区。此外，该策略可以很容易地应用于任何其他模型， SARS-CoV-2感染在不久的将来出现。

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.