Core B - Common Mouse Models Core (CMMC)

CORE B - Common Mouse Models Core (CMMC) – SUMMARY Aging is a predominant risk-factor for many chronic diseases in various tissues, thus further understanding the pathways and mechanisms underlying these disease states is of critical importance to human health. Although both p16Ink4a and p21Cip1 have been identified as key drivers of cellular senescence in various physiological and pathological contexts, the relative contributions of each towards age-related senescence across tissues in vivo remains unclear. The use of novel genetic mouse models and tools to further understand the role of p16Ink4a and p21Cip1 in cellular senescence across multiple tissues has been a key component of the previous PPG proposal. It is the overall goal of the Common Mouse Models Core (CMMC) (Core B) is to continue this high level of productivity and innovation by providing the common genetic and pharmacologic mouse model to the Projects [bone (Project 1), muscle (Project 2) and brain (Project 3)] and the various Cores. In Aim 1, the CMMC will test the effects of these important senescence-related genes by breeding the p16Ink4a and p21Cip1 single-, and the p16Ink4a;p21Cip1 double-gene floxed mouse models to a global, inducible R26-CreERT2 mouse driver, and treat with tamoxifen to induce the gene deletions. In Aim 2, we will test novel senolytic compounds that potentially confer tissue-specific and/or p16Ink4a- and p21Cip1- selective effects on senescence in aging across bone, muscle and brain in naturally aged wild-type mice. These senolytic compounds will be provided and tested for in vitro functionality by Core C. Additionally, in close coordination with Core C we will test these compounds for in vivo functionality. In both Aims 1 and 2, the CMMC work closely with Projects 1-3 and the Cores in the sacrifice and dissemination of mouse products for downstream analyses (Aim 3) within in each individual grant component. The CMMC will work closely with Core A to collect, curate and manage data related to the tissue sample collection, functional parameters, and histopathological findings. Since each of the Projects are using the same genetic and mouse models to understand cellular senescence across tissues, the CMMC serves to both coordinate and centralize activities to achieve high-quality data and reduce potential overlap and variability across these tissues by Projects 1-3 and the Cores in this PPG.