| Project Detail |
Mechanisms of communication in ageing
The Mechano-Ageing project, funded under the European Union HORIZON scheme, will “dig into the mechanics of ageing,” according to its principal investigator. Considering ageing as an altered state of communication between cells and the extracellular matrix (ECM), Mechano-Ageing will investigate where signalling goes wrong. The project will employ modern transcriptomics and functional tests in engineered cell lines to address an intriguing question: Can we rejuvenate cells by restoring the levels of key proteins involved in cell-ECM communication? The basic suspects, ECM proteins, may well represent new therapeutic targets for ageing-related pathologies.
"A recent work published by the host laboratory had redefined aging as a mechano-disease. Transcriptional co-factors YAP/TAZ, masters of mechanotransduction, were critical in stromal cells to prevent aging. Importantly, restoring cell-ECM communication and YAP/TAZ level was sufficient to ""rejuvenate"" old cells. Consequently, we hypothesize that the culprit of aging should be searched in ECM changes that drive the loss of mechanotransduction in stromal cells. Using single cell RNA-sequencing data of mouse dermal fibroblasts and mass-spec analyses of the dermis ECM during aging, we will seek for ECM candidates that may be at the root of this process. Then, we will build an Atlas of the mouse skin during aging using spatial transcriptomic and immunolabeling of mechanoresponsive proteins to unveiled new interconnections between the ECM and altered mechanotransduction during aging. As validation, we will use two complementary in vitro approaches. First, old mice fibroblasts will be culture on a young ECM synthetized by engineered young mice fibroblast lacking specific ECM genes, pinpointing to ECM proteins able to rejuvenate old cells. Second, we will generate 3D organotypic skin culture with keratinocytes and engineered dermal fibroblast lacking specific ECM candidate. We will ask whether it affects mechanosignaling and acquisition of aging traits in both dermis and epidermal compartments. Digging into the “mechanics of aging” is crucial because it would add a new paradigm on the causes of cell senescence and aging, define new markers for healthy aging and inform on new therapeutic perspectives to combat aging or some of its associated pathologies." |
