Mouse and Infection Models

Project Summary/Abstract The Mouse and Infection Models Core (Core B), will be directed by Dr. Hamilton Hart, with Dr. Niedernhofer as Co-I. This is an integral component of the PPG. The Core will be utilized by all three proposed projects and will allow PPG investigators to examine senescence and different immunological features of young and aged mice exposed to pathogens using both wildtype mice and genetically engineered mouse strains. Our recent studies determined that the vulnerability of aged mice to infection can be overcome with either short term senolytic treatment or genetic ablation of senescent cells, which reduced SASP levels and supported the development of anti- viral responses. This proposal will expand upon these novel findings and develop a mechanistic understanding of how the senescent cell burden, which increases with age and disease, affects the response of specific immune cell populations after infection. Core B will generate and validate stocks of acute viruses and expose mice to a diverse microbial milieu via pet store mouse fomite bedding. We will produce mouse lines composed of chronologically aged mice and comparison young mouse cohorts. We will also characterize and expand novel mouse models generated by Project 1 in which accelerated aging is driven in specific immune cells and in which cells expressing senescence markers p16 and p21 can be identified or inducibly ablated. Centralizing the breeding, maintenance, and expansion of these different mouse strains allows for comparison and standardization of results between the three inter-related projects and increased efficiency while reducing cost. Centralizing the infection paradigms and employing quality control standards will increase the rigor of experiments. Lastly, to further ensure rigor and reproducibility, Core B will utilize a unique data base called MouseCloud, to track mice and tissues as they are generated and distributed for use by the Projects and Core C. These unique tools will be used to test project-specific hypotheses focused on how senescence in distinct cell types contribute to immune dysfunction.