Researchers at the UConn Center on Aging at UConn Health and the Jackson Laboratory for Genomic Medicine (JAX) in Farmington, in collaboration with other researchers from several major health and research institutions, received funding from the National Institutes of Health (NIH) to participate in a study of rare types of cells, called senescent cells, which play an important role in biological processes associated with aging. This $ 13.5 million award (U54 AG075941) is titled KAPP-Sen Tissue Mapping Collaborative, given the researchers’ emphasis on studies to map senescent cells in the kidneys, adipose tissue, the human pancreas and placenta.

The ability of human cells to divide in half is a fundamental feature of development which in some cases continues throughout an individual’s life. However, in a series of seminal studies conducted in the 1960s, Dr Leonard Hayflick showed that normal cells can only undergo a limited number of divisions before they stop dividing and enter a state of senescence. replicative.

More recent research has shown that these apparently dormant senescent cells are far from benign and in fact play an important role in health as the drivers of many different chronic diseases, either directly or through the release of molecules that can affect both neighboring and distant cells. As a result, it is increasingly believed that senescent cells also contribute to the onset and progression of multiple chronic diseases and aging conditions such as cardiovascular disease, osteoporosis, frailty, and neurodegeneration.

Dr George Kuchel

“Cellular senescence is one of the main biological characteristics of aging,” says Dr George Kuchel, director of the UConn Center on Aging at UConn Health and principal investigator of the U54-funded project. “The use of animal models of aging and chronic disease has significantly advanced our understanding of cellular senescence and has led to the discovery of compounds called senolytics, which allow senescent cells to die and be eliminated by the body,” resulting in significant functional improvements. “

In view of these very promising animal studies, Kuchel adds, many of these interventions are now on the verge of entering proof-of-concept clinical trials in humans, while others are in various stages of preclinical testing. .

“Despite these remarkable advances,” Kuchel recalls, “very little is known about the presence, precise nature and relevance of senescent cells in human tissues, particularly in the absence of overt disease. We realized that we could make a significant contribution here at UConn and through our research partners at JAX, but it was too big for ourselves – we had to work closely with several surgical centers, including the heads of file transplants, to ensure the necessary solid human tissue pipeline. to make real progress in research.

The senescence mapping research they are conducting, says Kuchel, includes four types of tissue, including healthy samples from human kidneys, pancreas, placenta and adipose tissue. Team members across the country, he says, will collect these samples as part of the surgical and transplant procedures, and ship them to Farmington, where the tissues will be cataloged and analyzed, and the results published in the database. national data.

“This grant is a huge and extremely important step to better understand the mechanics of senescent cells,” Kuchel said. “Single-cell analysis allows us to collect and separate cells within tissues to examine the properties of each cell in detail, ‘cartoning’ each component to better understand how they work and, over time, develop drugs. which will limit their negative effects. and accentuate their positive properties. The NIA Translational Geroscience Network, of which UConn is one of the eight founding institutions, currently supports more than 40 clinical trials testing such compounds in humans. However, this grant will help propel the field in new directions. “

Research collaborators include the Joslin Diabetes Center, the Brigham and Women’s Hospital in Boston, the Mayo Clinic in Rochester, Minnesota, and the University of Texas Health Science Center in San Antonio.

The NIH pooled fund is providing $ 125 million to fund 16 grants over five years, including eight awards for the establishment of SenNet Tissue Mapping Centers, which include UConn Health, JAX, and their project partners. Tissue Mapping Centers will identify biomarkers of senescent cells in humans, then build detailed, high-resolution maps of cellular senescence throughout lifespan and physiological states, which will be shared via a national database. SenNet, creating a publicly accessible and searchable Cellular Data Atlas. Senescence. The SenNet program is a trans-NIH effort managed collaboratively by staff from the NIH Common Fund, the National Institute on Aging, and the National Cancer Institute.

Kuchel is the principal / contact principal investigator (PI). The team includes other multiple NPs, including Paul Robson of the Jackson Laboratory for Genomic Medicine; Dr. Nicolas Musi of the University of Texas at San Antonio Health Sciences Center; and Dr. Vesna Garovic at the Mayo Clinic.

It also involves many co-researchers, including Dr Stefan Tullius from Brigham and Women’s Hospital; Dr Cristina Aguayo-Mazzucato of Joslin Diabetes Center, an affiliate of Harvard Medical School; and Ming Xu at the UConn Center on Aging at UConn Health. Other contributors to Farmington include Dr Qian Wu of the Department of Pathology and Laboratory Medicine, who will be responsible for pathological tissue analysis, as well as Duygu Ucar and Jeff Chuang of JAX, who, along with Chia-Ling Kuo of UConn Health, will conduct the data analysis.

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