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Principal Investigator: Sara Elizabeth Hamilton Hart
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $517,948
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <AP20187><Ablation><Acute><Affect><Age><Aging><Animal Experiments><Anti-viral Response><Apoptosis-Related Cysteine Protease Gene Caspase 8><Apoptotic Cysteine Protease Gene><Apoptotic Protease MCH-5 Gene><Autopsy><Beds><Body Tissues><Breeding><C57BL/6 Mouse><CAP4><CAP4 protease><CASP8><CASP8 Protein><CASP8 gene><CDK4I><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CMM2><CRE Recombinase><Caspase-8 Gene><Caspase-8/Flice><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Senescence><Cell Signaling><Cells><Cellular Aging><Cellular Immune Function><Cellular Senescence><Chronology><Cyclin-Dependent Kinase Inhibitor 2A Gene><DNA Damage><DNA Excision Repair Protein ERCC-1><DNA Injury><DNA Repair Endonuclease><Data Bases><Databases><Dimerization><Disease><Disorder><Drug Therapy><Drug or chemical Tissue Distribution><Drugs><ERCC1><ERCC1 gene><Ensure><Enterobacteria phage P1 Cre recombinase><Excision Repair Cross-Complementation Group 1><Excision Repair Cross-Complementing 1><Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 1><Exposure to><FADD-Homologous ICE/CED3-Like Protease Gene><FADD-Like ICE><FADD-Like ICE Gene><FADD-homologous ICE/CED3-Like Protease><FK-506-Binding Protein><FK506 Binding Proteins><FKBP><FKBP Rotamase><FLICE><FLICE protein><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><GEM model><GEMM model><Genetic><Genetically Engineered Mouse><Goals><Hematologic Body System><Hematologic Organ System><Hematopoietic Body System><Hematopoietic System><ICE-Like Apoptotic Protease 5 Gene><INK4><INK4A><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><In Vitro><Infection><Intracellular Communication and Signaling><Intravenous><Investigation><Investigators><Laboratory mice><LoxP-flanked allele><MACH protein><MACH-Alpha-1/2/3 Protein Gene><MACH-Beta-1/2/3/4 Protein Gene><MCH5><MCH5 Isoform Alpha Gene><MHC Receptor><MORT1-Associated CED-3 Homolog Gene><MORT1-Associated CED3 Homolog Gene><MTS1><MTS1 Genes><Maintenance><Major Histocompatibility Complex Receptor><Mch5 protease><Measurement><Mediating><Medication><Methods><Mice><Mice Mammals><Microbe><Modeling><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Mouse Strains><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><NIAID><National Institute of Allergy and Infectious Disease><Ovalbumin><Peptides><Pharmaceutical Preparations><Pharmacotherapy><Phenotype><Polyadenylation><Population><Protein Dimerization><Quality Control><RAD10><RNA Polyadenylation><Replicative Senescence><Reporter><Reproducibility><Research Personnel><Research Resources><Researchers><Resources><Role><Signal Transduction><Signal Transduction Systems><Signaling><Specific qualifier value><Specified><Standardization><T-Cell Antigen Receptors><T-Cell Receptor><TP16><TSG9A><Tacrolimus Binding Proteins><Testing><Tissue Banks><Tissue Collection><Tissue Distribution><Tissue repository><Tissues><Titrations><Transgenic Mice><Transgenic Organisms><VSV><Vendor><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Virus><Wild Type Mouse><Work><accelerated aging><accelerated biological age><accelerated biological aging><adverse consequence><adverse outcome><age acceleration><aged><aged mice><aged mouse><ages><animal experiment><anti-viral development><anti-viral drug development><anti-viral therapeutic development><anti-viral therapy development><antiviral development><antiviral drug development><antiviral therapeutic development><antiviral therapy development><bacteriophage P1 recombinase Cre><biological signal transduction><caspase-8><cell type><cohort><cost><cost effective><data base><developing anti-viral agent><developing anti-viral drug><developing anti-viral therapeutic><developing anti-viral therapy><developing antiviral agent><developing antiviral drug><developing antiviral therapeutic><developing antiviral therapy><drug treatment><drug/agent><elderly mice><experience><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><flow cytophotometry><floxed><floxed allele><genetically engineered mouse model><genetically engineered murine model><host response><immune function><immune system function><immune system response><immunoresponse><improved><innovate><innovation><innovative><microbial><mortality><mouse model><murine hepatitis coronavirus><murine model><necropsy><novel><old mice><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><pathogen><pathogen exposure><postmortem><programs><promoter><promotor><response><scRNA-seq><senescence><senescent><senescent cell><senolytics><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><tool><transgenic><wildtype mouse>