Effect of Aging on Urothelial Function

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 DESCRIPTION (provided by applicant): Lower urinary tract symptoms (LUTS), in particular storage symptoms (urinary incontinence) are a major health related problem in the elderly. LUTS remain largely under diagnosed and poorly managed by healthcare providers and incontinence has been cited as the major reason for institutionalization of the elderly. There is little information to explain how aging alters normal bladder physiology, and how these changes contribute to the etiology of LUT disorders in the elderly. Much of research past and present, has focused on detrusor muscle function and changes in the central neurological control of aging-related LUT function; however, much less is known about the role of the urothelium in these events. While previously known of as a simple barrier, the urothelium is associated with the nervous system and sensory input arising at the apical surface of the umbrella cell layer regulates bladder function to the CNS via a local urothelial-afferent signaling pathway. Changes in sensory mechanisms are important in older persons diagnosed with overactive bladder or incontinence. The goals of this project are to explore the effect of aging and age-related processes (such as changes in blood flow) on urothelial-related functional elements in the bladder wall. Our preliminary data show that aging correlates with altered urothelial expression of mediators, decreased vascular perfusion and inability to regenerate the urothelium after injury, all of which can adversely impact sensation and bladder function. Thus, our overall hypothesis is that aging involves altered urothelial-afferent signaling that can result in symptoms of bladder overactivity and failure to store urine leading to incontinence or underactivity and retention in the elderly. Our multidisciplinary research team will elucidate the effect of aging o urothelial remodeling in the bladder and cross talk between bladder wall layers and sensory function. We will have unprecedented access to human information (patient registries, bladder biopsies, functional imaging) that will aid us in designing and interpreting the observations as well as stimulating translational application of this research, using an aging (3- 30 mo) rat model. In Aim #1, we will characterize mechanisms by which aging (and changes in blood flow) affects urothelial cell barrier functions by measuring transepithelial resistance and permeability. We will also assess vascular perfusion and explore the involvement of trophic factors on barrier functions. Aim #2 will characterize mechanisms underlying aging changes in urothelial sensory functions using functional assays and molecular techniques. Finally, Aim #3 will characterize mechanisms by which aging affects communication in the bladder wall. We will examine mechanisms underlying these changes by use of afferent nerve recording including use of viral-constructs to label afferents and optical mapping techniques to examine cell-cell interactions in the bladder wall. In sum, our intriguing preliminary data, combined with our extensive expertise and resources (including mathematical and computer modeling), places our research team in a unique position to examine mechanisms that may be responsible for underlying symptoms (overactivity; inability to empty) involved in the aging bladder.