The ultimate objective of the Animal Models Core is to support a highly interactive program that will explore and explain the role of natural variation in susceptibility to highly pathogenic, newly emerging respiratory viruses. Specifically the Core will generate mouse lines that are optimized for unbiased genome-wide testing of the effect of host genetics in susceptibility to respiratory viruses. These lines are designed such that mice can be replicated to test temporal effects, every line is equally compatible with use of common immunological reagents and the overall population has maximum level and random distribution of functionally relevant genetic polymorphisms. Mice will be derived by intercrossing or out crossing recombinant inbred lines from population known as the Collaborative Cross. The Collaborative Cross is a mammalian reference population that was designed to provide a cross-disciplinary platform for systems genetics in the most popular mammalian model organism, the mouse, and to overcome limitations of existing platforms. The Core will also provide regular updates with increasing levels of detail and accuracy on the genome of the mice used in this project starting with very dense genotypes and ultimately de novo assembly of the whole genome sequence of each line.
Our specific aims are: 1) Generate and distribute to each of the four scientific projects with 150 CC lines that are optimized genome wide mapping of loci that control host genetics susceptibility to respiratory viruses;2) Generate data for baseline immunological parameters to be used case-control comparisons across projects;3) Generate and maintain quarterly updates of the genome sequence of mouse lines used on this project and 4) Generate and distribute mice that are optimized for validation studies in the second phase of the project.
Host genetics plays a key role in differential response to infectious diseases. The development of animal models will provide a tool to understand how genetic polymorphisms and gene interactions differentially regulate targeted immune outcomes, crosstalk between immune components, extreme immune phenotypes, and initiate protective or pathogenic immune responses following virus infection. Our study will complement and inform our understanding of human disease and provide a straight forward with to causal inference.
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