Impact of Cellular Senescence on the Development of Pelvic Organ Prolapse

About This Grant

PROJECT SUMMARY Pelvic organ prolapse (POP) is an age-related disorder that affects up to 50% of women impacting quality of life and resulting in exorbitant healthcare costs. On a cellular level, the process of aging is termed cellular senescence and it has been associated with degenerative and age-related diseases. Despite current studies suggesting a link between POP and cellular senescence there is a lack of understanding of how senescence- associated changes contribute to the development of prolapse. In this application we will test the hypothesis that induction of cell senescence culminates in POP during aging. To accomplish this, we will use state-of-the art methodologies (single-cell and single-nuclei RNA sequencing; biomechanical phenotyping considering both contractile and non-contractile properties) to reveal new facets of cell senescence signaling pathways in the vagina with age and known development of prolapse. We will employ a translational approach that combines both human research and animal models, which will allow for longitudinal follow-up that is not feasible in humans. Our specific aims are to (1) identify the differential gene expression and extracellular matrix regulation of age- related POP using an animal model, (2) determine if vaginal contractile potential and biomechanical stability are rescued in a novel mouse model of prolapse and cellular senescence, and (3) link extracellular matrix composition with cell senescence in vaginal stromal tissues from women with and without prolapse. The research proposed here will help define the mechanism of cell senescence in initiating the path of loss of pelvic organ support during aging. Identification of cellular pathways and unique cell populations associated with the development of prolapse can result in the design of interventional strategies that can prevent or slow the progression of cell senescence and in turn prevent development of POP. Successful execution of the aims of the proposed study will transform pelvic floor medicine and inform other aspects of the biology of aging.