U54AG075934

Washington University Senescence Tissue Mapping Center (WU-SN-TMC) - Overall Project Summary/Abstract

Cellular senescence has been characterized as a state of irreversible cell-cycle arrest coupled with a secretory program that can profoundly impact the tissue microenvironment. Our current understanding of senescence is largely based on cell culture and model-based studies. Research on the relevant signaling pathways and mechanisms underlying cellular senescence across human tissues over time is lacking.

Our ability to leverage recent advances in omics and molecular imaging technologies enables us to investigate the transcriptional changes and secretory features driving and/or associated with senescence at higher depths and resolution than ever before. Here, we propose to develop the Washington University Senescence Tissue Mapping Center (WU-SN-TMC) within the NIH Senescence Network (SENNET).

Our WU-SN-TMC will develop cellular senescence atlases using 500 human samples from four essential tissue types: bone marrow, breast, colon, and liver. We will first optimize our omics and imaging technologies and platforms for capturing, detecting, characterizing, and visualizing senescent cells. We will also develop computational tools and models for accurate identification of senescent cells and markers. Additionally, we will construct breast, bone marrow, colon, and liver senescence atlases in spatial and temporal contexts, and assess the landscape and heterogeneity of senescence.

With these initial atlases, we will further characterize, validate, and define cellular senescence phenotypes and biomarkers using perturbation methods. We will also investigate the interactions between senescent cells and the senescence-associated microenvironment. Finally, we will work with other SENNET centers to build comprehensive, major organ/tissue senescence atlases by integrated and comparative studies of all SENNET data across tissue types, time, sex, age, and ancestry groups.

As a member of the SENNET program, WU-SN-TMC will employ state-of-the-art omics and imaging technologies, including bulk proteogenomics, single-cell sequencing, spatial transcriptomics, CODEX molecular imaging, and 3D light sheet microscopy plus expansion technologies. These technologies are likely to mature over the funding period, such as single molecule sequencing, to generate high-resolution, multi-parameter biomarkers and maps of cellular senescence in the four tissue types selected.

We have the established infrastructure and expertise to successfully conduct this work, including high-quality biospecimen collection, omics and imaging data production, experimental confirmation and validation, and high throughput, standardized, and reproducible data analysis.

In conclusion, we will work closely with other SENNET centers and the Consortium Organization and Data Coordination Center (CODCC) to generate comprehensive atlases across major human tissue types under various physiological conditions, including changes across the human lifespan.

Washington University

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]

Saint Louis, Missouri 631101010 United States

Single Zip Code

Cellular Senescence Network: Tissue Mapping Centers (U54 Clinical Trial Not Allowed) (RFA-RM-21-008)

Amendment Since initial award the total obligations have increased 300% from $1,500,000 to $5,999,999.