The Mutant Mouse Core (Core B) is an essential core that will be used extensively by all three projects. Given the complex interplay between different inhibitory receptors on multiple cell types, the only way one can dissect these critical disease-related biological questions in vivo is with sophisticated mouse models. A significant strength of this PPG application is the unique `surgical' tools that it will utilize, specifically PD1/LAG3 floxed mice combined with a unique collection of lineage-specific, and in some instances temporally controlled, Cre recombinase-expressing mice. These tools will give us unprecedented control and thus insight into PD1/LAG3 synergy and function in multiple cell types.
AIM 1 : To provide the PD1/LAG3 mutant mice required for the PPG. The Core will be administered from UPitt, with the majority of the mutant mouse breeding and procurement outsourced to Taconic under Murine Pathogen Free barrier conditions identical to the majority of their commercial breeding practices. Taconic will deliver mice to all research sites on a rotating weekly basis using their conventional delivery mechanism, thereby avoiding lengthy quarantine.
AIM 2 : To generate new mutant mouse combinations. The Core will generate of new mutant mouse combinations that introduce different genetic elements such as new Cre stains and TCR transgenes. PPG Interactions: Core B will support Project 1, Project 2 and Project 3 extensively, and interact with Core A to provide easy access to breeding, shipping and genotyping data. Core B will also perform additional crosses to generate any stain combinations required by the projects. Core B will interact with Core A to provide easy access to breeding, shipping and genotyping data, and ongoing monitoring.
The inhibitory receptors PD1 and LAG3 synergize to limit autoimmune disease. However, they are also over expressed in cancer and chronic viral infections, preventing disease clearance. Although PD1 and LAG3 are now major therapeutic targets, it is not clear how they mediated this synergistic regulation and on which cells types. A greater understanding of these issues could lead to move effective therapeutic strategies. Core B will provide mutant mice to all the projects and is essential.
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