U54AG079758

Spatial Mapping Senescent Cells Across the Mouse Lifespan by Multiplex Transcriptomics and Epigenomics - Project Summary

Cellular senescence, characterized by stable proliferation arrest and secretion of pro-inflammatory factors, is not only a hallmark of aging but also a key contributor to age-associated diseases in humans. As the US population is aging, there is an added urgency to gain a better understanding of cellular senescence in different tissues over the lifespan.

Unfortunately, we still lack the knowledge to unambiguously define senescence at the molecular and cellular levels due to its heterogeneous phenotypes. To address this major gap in knowledge, we propose to establish a tissue mapping center that focuses on the identification and characterization of senescent cells in healthy mouse brain, bone marrow, breast, colon, and liver.

Our research strategy builds on recent advances in single-cell epigenomics technologies that our team developed and the knowledge that senescent cells exhibit characteristic changes in the chromatin landscapes and histone modifications along with gene expression levels at marker genes of cellular senescence.

We will deploy cutting-edge single-cell in situ and tissue dissociative multi-omic tools that have been well established in our center to produce comprehensive single-cell resolution maps of the transcriptome and epigenome in male and female mouse brain, bone marrow, breast, colon, and liver. Additionally, we aim to provide qualitative and quantitative spatial maps of the normal burden of senescent cells in these vital organs across the lifespan of two mouse strains.

We will rigorously validate the newly defined senescent cell populations using pharmacologic and genetic approaches to eradicate senescent cells or suppress their inflammatory phenotype. We will also employ orthogonal state-of-the-art and conventional assays for cellular senescence.

Furthermore, we will generate whole-genome single-cell DNA methylation data to link our spatial atlas to the measurement of epigenetic age, a candidate predictor of beneficial versus detrimental effects of senescent cells.

We expect that comprehensive single-cell atlases of the epigenome and transcriptome will enable us to identify and characterize cellular senescence in different tissue contexts and during aging. Moreover, we anticipate that the planned research will provide a reference for future studies that seek to characterize and target senescent cells associated with or preceding disease in the brain, bone marrow, breast, colon, and liver.

Sanford Burnham Prebys Medical Discovery Institute

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Institute on Aging (NIA) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

La Jolla, California 920371005 United States

Single Zip Code

Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272)

Amendment Since initial award the total obligations have increased 322% from $2,566,784 to $10,836,434.