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

 描述(由申请人提供)： 我们的建议侧重于新的药物干预策略，以改善患有尿失禁的老年退伍军人的生活质量。随着老年退伍军人人数的快速增长，这将成为退伍军人医疗保健系统的重大健康负担。尿失禁(UI；非自愿性尿漏)影响了大量的男性和女性(&gt；15%)，发病率随着年龄的增长而增加。这是一种严重影响人们生活质量的疾病。尿路括约肌和盆底肌肉(PFM)在尿控机制中起着重要作用，这些肌肉中与年龄相关的退行性改变被认为是老年人群尿失禁最常见的原因。PFM(女性)或尿道括约肌(男性)的损伤被认为是括约肌复合体功能障碍的重要原因。我们假设，在晚期衰老过程中观察到的括约肌复合体损伤后肌肉再生受损以及纤维化/肌肉萎缩的增加是由一种新的分子途径(Wnt-ücatenin信号)介导的。清楚地了解这些与括约肌纤维化/萎缩有关的分子机制将有助于开发创新的策略来治疗老龄化人口中的这种疾病。我们的初步动物(兔)研究证实了我们的假设，并建议靶向Wnt信号通路可以减轻括约肌萎缩/纤维化和改善肌肉功能。我们的具体目标是：1)确定WNT/？-catenin信号通路在手术损伤后新生肌肉纤维再生、纤维化形成和EAS肌功能及其构筑中的作用；2)评价衰老对尿道/PFM肌功能的影响，确定W-NT信号通路在增龄相关退行性改变中的作用；(A)使用新型磁共振扩散张量成像(DTI)评估男性前列腺癌患者自愈前和自愈过程中的尿路括约肌复合体的肌肉构筑；(B)将大小便失禁恢复的时间进程与年龄和解剖缺陷相关联。我们预计，从这些研究中学到的原则将有助于识别新的治疗策略，以防止年龄相关性括约肌退化，并改善老年老兵人口的可控性。这项建议承诺解决在了解与年龄相关的尿道括约肌复合体功能障碍及其病理生理学方面的关键临床挑战，并提供一种新的多功能药物来预防/治疗这种影响许多老年男性和女性生活质量的疾病。我们的建议是创新的概念(与损伤相关的括约肌功能障碍是由于肌肉再生错乱、过度的胶原沉积和肌纤维方向紊乱所致)。过度纤维化是由Wnt信号增加引起的)，一种新的方法(使用Wnt信号拮抗剂进行药物干预以改善括约肌功能)和新的工具(新型高清晰度测压和MR-DTI来研究再生肌肉中的括约肌功能和肌结构)。总而言之，拟议的研究实现了奖项中描述的目标，因为它具有很高的临床转化潜力(潜在使用W NT拮抗剂)，以最大限度地提高老年退伍军人的功能恢复(尿控功能)。

 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.