Regulatory Mechanisms in a Homeostatic Model of Geriatric Voiding Problems and Incontinence

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Urinary symptoms become more prevalent with advancing age, and contribute to social isolation, institutionalization and morbidity. Current pharmacologic approaches are directed at correcting abnormalities of bladder pressure and frequently prove ineffective and/or poorly tolerated. Furthermore, many older adults are asymptomatic yet exhibit bladder functions often considered abnormal. Standard formulations relating symptoms, function and therapeutics are insufficient to address urinary control problems, especially within the complex multisystem nature of urinary dysfunction in the elderly. The transduction of bladder volume to sensory afferent activity underpins control of the lower urinary tract. Recent evidence suggests that the transduction of bladder volume to bladder afferent activity is an adjustable gain system under continuous autonomic influence. Autonomic regulation of detrusor myocyte activity is a key factor in determining sensitivity of the transduction process. A key target is the mechanism of autonomic control over detrusor myocyte activity and therefore the sensitivity of volume sensory transduction. A network of Cx43 gap-junction linked interstitial cells (IC) is postulated to be a control network, mediating the autonomic regulation of detrusor myocyte activity. These cells have recently been found to express the molecular analog of the “funny current” involved in pacemaker functions, the Hyperpolarization gated, Cyclic Nucleotide activated (HCN) channel. HCN channels have a high propensity for modulation by transmitters of the autonomic nervous system and therefore, we hypothesize that HCN channels in IC cells contribute to autonomic regulation of bladder tension. Age-associated change in HCN isoform expression exists in other tissues, and could result in altered autonomic detrusor control of older bladders. We have recently developed a flow cytometry technique permitting isolation and electrophysiologic study of individual ICs. Using analytic tissue studies, cellular and molecular biology tools and electrophysiologic patch clamp techniques, we propose to determine the role of HCN in autonomic regulation of IC-based mechanisms controlling detrusor tension in an established mouse system. We will further test the impact of aging on these mechanisms via loss or isoform change in HCN expression, and provide tissue-level descriptive confirmation of mechanistic models. This work integrates institutional expertise in physiology/cystometry, gerontology, geriatrics, immunology, and neurophysiology, making use of excellent core services in flow cytometry, histology, electrophysiology and ultimately single cell genomics. The focused training provided by this Award represents the final step in the career development of the PI and will provide important preliminary data for planned R01-level grant writing later in 2016 and beyond.