Targeting Wnt Signaling Pathways to Treat Age-Related Anal Incontinence

描述(由申请人提供)： 我们在此的建议将侧重于在退伍军人中康复“年龄相关性肛门失禁”的新的药理学策略，女性退伍军人是退伍军人保健用户中增长最快的部分。年龄相关性肛门失禁是女性人群中的一种主要疾病(&gt；7%)，但报道不足。这种疾病的确切机制尚不清楚。肛门失禁最常见的原因是由各种机制引起的与分娩相关的肛门外括约肌(EAS)损伤，即拉伸、缺血、自发性撕脱和手术切开(会阴切开)。与年龄相关的肛门括约肌退行性改变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。清楚地了解EAS肌肉损伤后肛门失禁的分子机制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在 肛门失禁患者提示与年龄相关的EAS肌肉功能受损(长度-张力特性)。在动物模型中，这种肌肉功能障碍与再生肌肉中纤维化增加和纤维方向紊乱有关。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损伤后的老年动物和幼年动物中，WNT(？-catenin)信号增加。此外，注射细胞外Wnt拮抗剂分泌型相关卷曲蛋白2(SFRP2)可改善损伤后EAS的肌肉功能。我们的假设是，Wnt信号的增加是肛门括约肌损伤后肌肉再生受损的主要驱动机制，以及在老年过程中观察到的括约肌退行性变化的增加。靶向Wnt信号通路可以减轻括约肌纤维化，改善肌肉功能。我们的具体目标是：1)确定Wnt/β-catenin信号通路在肌切开术后新生肌纤维再生、纤维化形成和EAS肌功能中的作用。2)评价增龄对EAS肌肉功能的影响，探讨Wnt信号通路在增龄相关退行性改变中的作用。我们预计，从这些研究中学到的原则将有助于确定新的治疗策略，以防止与年龄相关的括约肌退化，并改善老年女性退伍军人的可控性。总而言之，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(潜在使用Wnt拮抗剂)到 最大限度地恢复老年退伍军人的功能(肛门控制功能)。

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.