Mechanosurveillance of senescent cells
Active Project Grant Awarded Last action
- Award ID
- F31AG104368
- Recipient
-
Weill Medical College Of Cornell University UEI YNT8TCJH8FQ8
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 0% complete
- Place of performance
- New York, NY 10065, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cellular senescence is a stress response that plays important roles in homeostasis and disease. The immune system's ability to recognize and eliminate senescent cells is essential for maintaining homeostasis, but little is known about this process. While prior research has focused on how biochemical changes during senescence programming (e.g. stimulatory ligands, cytokine secretion, etc.) may influence the identification and clearance of senescent cells, few studies have examined the effects of biomechanical changes on immune targeting. The huse lab has demonstrated that lymphocytes preferentially destroy stiffer cancer cells, indicating that lymphocytes respond to both biochemical cues and biophysical properties of their targets. We have termed this mechanical dimension of immunosurveillance, "mechanosurveillance." this proposed work will investigate the biomechanical phenotype of senescent hepatocytes and how IT impacts mechanosurveillance. Our preliminary data has shown that senescent cells exhibit increased formation of F-actin stress fibers, and that this unique cytoskeletal architecture makes them more rigid than their non-senescent counterparts. We have also found that senescent cells are more stimulatory to cytotoxic T cells in vitro and, most importantly, attenuating the F-actin cytoskeleton in senescent cells dampens this stimulatory response. Building upon these preliminary data, I hypothesize that the unique morphology of senescent cells sensitizes them to mechanosurveillance and plays a critical role in their clearance in vivo. I will continue to investigate this hypothesis in two specific aims. In aim 1, I will use in vivo senescence modeling, novel mechanical profiling technology and single-cell RNA-sequencing to characterize the mechanoselection of senescent hepatocytes and uncover the mechanisms that drive senescence-associated cytoskeletal remodeling. In aim 2, I will establish a complex mechanobiological mouse model that will enable me to perturb the F-actin cytoskeleton in senescent cells. This tool will decouple the biochemical determinants from the biophysical in the immunosurveillance process, enabling the examination of the necessity of senescence-associated cytoskeletal remodeling in their clearance. In doing so, I will provide insights into senescent hepatocyte clearance and potentially uncover therapeutic targets to combat aging.
Quick answers
Who received award F31AG104368?
F31AG104368 was awarded to Weill Medical College Of Cornell University by National Institute on Aging (National Institutes of Health) on February 20, 2027.
How much is award F31AG104368 worth?
$50,114 has been obligated on F31AG104368.
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