Midwest Murine-Tissue Mapping Center (MM-TMC)

PROJECT SUMMARY Senescent cells (SnCs) play a causal role in aging and numerous age-related diseases. However, they also contribute to beneficial biology such as wound healing and tissue remodeling. Both physiological and pathological roles are linked to the secretome of SnCs and their complex interaction with the immune system, which is thought to play an important role in clearing SnCs. Much of what has been learned about SnCs is derived from studies in mice, where it has been clearly demonstrated that genetic or pharmacologic removal of SnCs in aged or diseased organisms reduces frailty; improves strength, endurance, and resilience; and attenuates a variety of age-related diseases, including Alzheimer’s. Discovering pharmacologic approaches to remove disease-causing SnCs in humans could have a tremendous impact on our aging population. However, much needs to be learned about SnCs to deploy such approaches safely and effectively in humans. This project aims to establish a Tissue Mapping Center (TMC) across multiple institutions with demonstrated expertise in SnCs and cell mapping to achieve a common goal; construction of a 4D atlas of SnCs in mouse tissues. The Midwest Murine-TMC (MM-TMC) proposes to focus on 5 key tissues: mouse liver, adipose, lung, muscle, and brain. This selection is based on MM-TMC’s expertise in the biology, cell biology, and immunology of these organs; lengthy experience studying SnCs in these organs; and applying single cell and spatial technologies to study these organs. The MM-TMC and its Administrative Core will be led by PIs with complementary expertise in organ biology and senescence. The Biological Analysis Core will be led by three MPIs who have a long history of collaboration around studying SnCs in aged mice and working with unique and innovative transgenic animals that enable the production or ablation of lineage-specific SnCs. The Data Analysis Core will be led by two bioinformaticians with expertise in single cell analysis, cell mapping, and multiplexing complex and disparate data sets to deeply phenotype cells. Other key personnel add expertise in pathology, imaging, spatial mapping of SnCs, tissue clearing, transgenic mice, and development of senolytics and immunotherapies to target SnCs. A unique feature of the proposed MM-TMC is that the data collection will be done within existing cores largely at the University of Minnesota by staff with expertise in state-of-the art spatial mapping platforms. This provides stability in the analytical pipeline and in-place quality control and assurance mechanisms. Through systematic and methodical study of SnCs in mouse tissues, the MM-TMC will make significant contributions informing and validating the SenNet human atlas and will work closely with NIH, other TMCs, Technology Development awardees, and the Consortium Organization and Data Coordinating Center to develop and adhere to standards created by SenNet to accelerate the production of rigorous SnC tissue maps in both species.