Detrusor Underactivity as an HCN-mediated Failure of Resilience in Aging

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ABSTRACT Detrusor Underactivity (DU) is a voiding impairment due to insufficient bladder muscle effort to ensure timely and efficient bladder emptying. As a disorder of volume management, DU is often associated with incontinence and other urinary symptoms, especially in later life. Despite the term suggesting a bladder muscle disorder, a key characteristic of DU is loss of sensitivity to bladder volume. Like DU, aging is also associated with loss of volume sensitivity. Moreover, aging is characterized by increasing risk of failure to adapt to biologic challenge, i.e. loss of resilience. We therefore propose that DU is not a detrusor disease, rather it is a manifestation of the nonresilient end of the spectrum of bladder sensory changes of aging. In this project we will investigate the role of a “pacemaker” ion channel in the age evolution of a control mechanism critical to bladder volume sensitivity. We hypothesize that DU is associated with the more severe age- associated changes. This knowledge will allow us to determine the control factors contributing to the loss of successful, resilient aging and the resulting non-resilience manifested as DU. To accomplish these goals will use our established mouse cystometry model to test urinary resilience and define a DU group separate from age groups. Our research methods will include single cell genomic sequencing, electrophysiology, molecular/cellular investigations, and correlative tissue-level experiments in order to address our objective. By taking advantage of the uniquely available combined expertise within the UConn Center on Aging, Neurosciences department, and on-site Jackson laboratory, we will address the goal of identifying DU pathophysiology and contributing to an improved therapeutic model which recognizes DU as an adaptive failure.