Aging & Urethral Sphincter Dysfunction: Role of Wnt-B Catenin Signaling Pathways



 DESCRIPTION (provided by applicant): Our proposal focuses on novel pharmacological interventional strategies to improve the quality of life in the aging Veteran population afflicted with urinary incontinence. As the population of elderly veterans grows rapidly, it is poised to become a significant health burden on the VA Healthcare System. Urinary incontinence (UI; involuntary leakage of urine) affects a large number of men & women (>15%) and the incidence increases with age. It is a major medical illness that adversely affects one's quality of life. Urethral sphincters as well as pelvic floor muscles (PFM) play important roles in urinary continence mechanisms and age-related degenerative changes in these muscles are recognized as the most common cause for UI in the geriatric population. Injuries to the PFM (women) or to the urethral sphincters (men) are recognized as a significant cause for the sphincter complex dysfunction. We hypothesize that impaired muscle regeneration after the injury of the sphincter muscle complex as well as increased fibrosis/ muscle atrophy observed during advanced aging is mediated by a novel molecular pathway (Wnt -ß catenin signaling). A clear understanding of these molecular mechanisms involved in sphincter fibrosis/atrophy would enable the development of innovative strategies to treat this disorder in the aging population. Our preliminary animal (rabbit) studies confirm our hypothesis and suggest targeting Wnt signaling pathways could attenuate sphincter atrophy/fibrosis and improve muscle function. Our specific aims are: 1) To determine the role of Wnt/ß- catenin signaling pathways in the regeneration of new muscle fibers, formation of fibrosis/ and EAS muscle function and its architecture following surgical injury; 2) To evaluate the effect of aging on the urethral/ PFM muscle function and determine the role of W nt signaling pathways in the age related degenerative changes on the muscle function; (3). (A) To evaluate the myo-architecture of urethral sphincter muscle complex using novel MR- diffusion tensor imaging (DTI) before and during spontaneous healing process in men undergoing prostatectomy; (B) correlate time course of continence recovery with age and anatomical defects. We anticipate that the principles learned from these studies will enable the identificatio of novel therapeutic strategies to prevent age-related sphincter degeneration and also improve continence in the aging Veteran population. This proposal promises to address a critical clinical challenge in the understanding of age-related urethral sphincter muscle complex dysfunction and its pathophysiology as well as to deliver a novel multifunctional pharmacological agent for prevention/ management of this disorder that impacts the quality of life of many older men and women. Our proposal is innovative with novel concepts (sphincter dysfunction related to injury is due to deranged muscle regeneration, excessive collagen deposition and disorganized muscle fiber orientation. Excessive fibrosis is driven by increased Wnt signaling), a novel approach (pharmacological intervention with Wnt signaling antagonist to improve sphincter function) and novel tools (novel high definition manometry and MR-DTI to study sphincter function and myo-architecture in the regenerating muscle). In summation, the proposed study fulfills the objectives described in the award as it has high potential for clinical translation (potential use of W nt antagonists) to maximize functional recovery (urinary continence function) in the aging Veteran population.