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Most cells in the human body can divide and multiply to replace old cells and repair damaged tissue, but in response to certain stresses, cells can lose their ability to proliferate.
The rare cells that lose this ability are called senescent. They accumulate with age and might contribute to cancer and age-related disorders such as chronic lung disease, cardiovascular disease, frailty and dementia by pumping out signals that damage neighboring tissues.
The molecular landscape of senescence has remained relatively uncharted.
To address this knowledge gap, the National Institutes of Health’s Common Fund established the Cellular Senescence Network (SenNet) Program with the goal of creating a “Google Maps” of the aging tissues of the body that any scientist can access. Today, the program announced it will award $125 million to 16 teams to form the new SenNet Consortium — and two of the projects are led by University of Pittsburgh and UPMC researchers, who will receive a combined $31 million over five years.
“Aging is in many ways medicine's final frontier,” said Anantha Shekhar, senior vice chancellor for the health sciences and the John and Gertrude Petersen Dean of the School of Medicine. “These grants are a testament to Pitt’s breadth and depth of expertise in the field of aging research and our strong inter-institutional collaborations with UPMC, the Pittsburgh Supercomputing Center and Carnegie Mellon University.”
SenNet’s core mission is to dive deep into the process of cellular senescence, decoding how it happens both biochemically and at the cellular level. Just as Google Maps provides detailed information about every locale it stores, SenNet will provide data and analysis about the process of senescence for cells, tissues and organs down to the molecular scale.
Toren Finkel, distinguished professor of cardiology and director of the Aging Institute at Pitt and UPMC, is leading the TriState SenNet Tissue Mapping Center, one of the two projects led by Pitt. It will contribute to the atlas by developing maps of senescence in heart and lung cells, which will be combined with maps from different organs created by other teams in the consortium.
Like molecular cartographers, the researchers will map gene expression and protein composition in senescent cells from human tissue slices and lab-grown mini organs, or organoids. They’ll compare different types of senescent cells from across the lifespan to characterize signposts, or biomarkers, of senescence. Finkel will collaborate with co-principal investigators Melanie Königshoff, a visiting professor of medicine at Pitt, Irfan Rahman of the University of Rochester and Ana Mora from The Ohio State University.
“We don’t know if cellular senescence is one thing or many things,” said Finkel. “An analogy is cancer: Lung cancer, pancreatic cancer and lymphomas are all very different, even though we call them all cancer. We want to understand how senescent cells triggered by different stresses and occurring in different tissues are similar and how they are different.”
The second SenNet project led by Pitt will create an organized and navigable atlas that is accessible to everyone. Jonathan Silverstein, a professor in the Department of Biomedical Informatics at Pitt and chief research informatics officer at Pitt and UPMC’s Institute for Precision Medicine; Phil Blood of the Pittsburgh Supercomputing Center, a joint research center of CMU and Pitt; and Ziv Bar-Joseph of the Carnegie Mellon University School of Computer Science will jointly lead the SenNet’s Consortium Organization and Data Coordinating Center (CODCC). They will build on previous success in managing The Human BioMolecular Atlas Program, a similar program that aims to map healthy human tissues at a cellular level.
The CODCC, in addition to managing the SenNet Consortium, will serve the crucial role of providing computing software and hardware that will knit together SenNet’s eight tissue mapping centers and seven technology development and application projects.
Focusing on data analysis and integration, the Pittsburgh-led center will set standards for data accuracy and provenance, provide reliable and expansive data storage, and disseminate data and analytical tools to help scientists make sense of what is expected to be a tsunami of information.
Eventually, the atlas of cellular senescence will be published online in an open-source repository, providing a publicly accessible and searchable database so that other researchers can explore these data to make new discoveries about senescent cells and how they contribute to human health.
“I think that the science of senescent cells is tremendously exciting because of their potential impact on a whole variety of diseases,” said Silverstein. “By doing the basic science of collecting all of this information and presenting it through SenNet, there is incredible potential to learn more about the role these cells play in disease and develop pharmaceuticals that target them.”
— Asher Jones