Targeting Wnt Signaling Pathways to Treat Age-Related Anal Incontinence

描述（由申请人提供）： 我们在此的建议将集中在新的药理学策略的康复“年龄相关的肛门失禁”的女性退伍军人人口，增长最快的部分VA医疗保健用户。年龄相关性肛门失禁是女性的主要疾病（>7%），但报道较少.这种疾病的确切机制尚不清楚。肛门失禁的最常见原因是分娩相关的肛门外括约肌（EAS）肌肉损伤，其机制多种多样，即，牵拉、局部缺血、自发性撕脱和手术切口（会阴切开术）。肛门括约肌的退行性变化进一步影响括约肌功能。许多患者在他们生命的第五个十年后出现症状，这种风险随着年龄的增长而增加。对EAS肌肉损伤后肛门失禁的分子机制有一个清晰的认识，将有助于开发治疗这种疾病的创新策略。我们在动物模型以及 肛门失禁患者提示年龄相关的EAS肌肉功能（长度-张力特性）受损。这种肌肉功能障碍与动物模型中再生肌肉中纤维化增加和纤维取向紊乱有关。这种损伤可能会因年龄相关的肌肉纤维化增加而加重。我们的研究表明，在EAS损伤后，衰老动物以及年轻动物中Wnt（<$-连环蛋白）信号传导增加。此外，注射分泌型相关卷曲蛋白2（Sfrp 2），一种细胞外Wnt拮抗剂，改善损伤后的EAS肌肉功能。我们的假设是，增加Wnt信号是肛门括约肌损伤后肌肉再生受损以及在晚期衰老期间观察到的括约肌退行性变化增加的中心驱动机制。靶向Wnt信号通路可以减轻括约肌纤维化并改善肌肉功能。我们的具体目标是：1）确定Wnt/β-catenin信号通路在手术切开术后新肌纤维再生、纤维化形成和EAS肌肉功能中的作用。2)评估衰老对EAS肌肉功能的影响，并确定Wnt信号通路在EAS肌肉功能的年龄相关退行性变化中的作用。我们期望从这些研究中学到的原则将能够确定新的治疗策略，以防止年龄相关的括约肌退化，并改善老年女性退伍军人人群的功能。总之，拟议的临床前研究实现了SPiRE奖中描述的目标，因为它具有很高的临床转化潜力（Wnt拮抗剂的潜在用途）， 最大限度地恢复功能（肛门功能）在老龄化的退伍军人人口。

DESCRIPTION (provided by applicant): Our proposal herein will focus on novel pharmacological strategies for the rehabilitation of "age-related anal incontinence" in the female Veteran population, the fastest growing segment of VA healthcare users. Age- related anal incontinence is a major medical condition in female population (>7%) which is under reported. The exact mechanism of this disorder is unclear. The most common cause of anal incontinence is childbirth related injury to external anal sphincter (EAS) muscle by a variety of mechanisms, i.e., stretch, ischemia, spontaneous avulsions and surgical incision (episiotomy). Age-related degenerative changes to anal sphincter muscles further impact sphincter functions. Many patients develop symptoms after the 5th decade of their life and this risk increases with advancing age. A clear understanding of the molecular mechanisms of anal incontinence after EAS muscle injury would enable the development of innovative strategies to treat this disorder. Our preliminary studies in animal model as well as in patients with anal incontinence suggest age-related impairment of EAS muscle functions (length-tension property). This muscle dysfunction is associated with increased fibrosis and disorganized fiber orientation in the regenerating muscle in the animal model. This impairment is likely to be aggravated by the age-related increase in the muscle fibrosis. Our studies demonstrate an increase in Wnt (¿-catenin) signaling in the aging animals as well as young animals following EAS injury. In addition, injection of secreted related frizzled protein 2 (Sfrp2) an extracellular Wnt antagonist, improves the EAS muscle function following injury. Our hypothesis is that, increased Wnt signaling is a central driving mechanism for impaired muscle regeneration following anal sphincter injury as well as increased sphincter degenerative changes observed during advanced aging. Targeting Wnt signaling pathways could attenuate sphincter fibrosis and improve muscle function. Our specific aims are: 1) To determine the role of Wnt/¿-catenin signaling pathways in the regeneration of new muscle fibers, formation of fibrosis/ and EAS muscle function following surgical myotomy. 2) To evaluate the effect of aging on the EAS muscle function and determine the role of Wnt signaling pathways in the age related degenerative changes on the EAS muscle function. W e anticipate that the principles learned from these studies will enable the identification of novel therapeutic strategies to prevent age-related sphincter degeneration and also improve continence in the aging female Veteran population. In summation, the proposed pre-clinical study fulfills the objectives described in the SPiRE award as it has high potential for clinical translation (potential use of Wnt antagonists) to maximize functional recovery (anal continence function) in the aging Veteran population.