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

老化

基本信息

批准号：
10174741
负责人：
MAHADEVAN Raj RAJASEKARAN
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-10-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174741
关键词：
Address Affect Age Aging Anatomy Animal Model Animals Architecture Atrophic Attenuated Automobile Driving Award Basic Science Bladder Control Childbirth Clinical Collagen Complex Controlled Study Defect Deposition Development Diffusion Diffusion Magnetic Resonance Imaging Discipline Disease Disease Management Elderly Extravasation Fiber Fibrosis Functional disorder Genes Goals Health Healthcare Healthcare Systems High Prevalence Image Impairment Incidence Injury Intervention Limb structure Longitudinal Studies Manometry Mediating Medical Military Personnel Modeling Molecular Morbidity - disease rate Morphology Muscle Muscle Fibers Muscle function Muscular Atrophy Natural regeneration Operative Surgical Procedures Oryctolagus cuniculus Pathway interactions Patients Pelvic Floor Muscle Pharmacology Play Population Prevention Process Prostate Prostatectomy Provider Quality of life Recovery Recovery of Function Role Science Signal Pathway Signal Transduction Sphincter Surgical Injuries Techniques Testing Time Translational Research Urethra Urethral sphincter Urinary Incontinence Urine Urology Veterans WNT Signaling Pathway Woman age effect age related aging population beta catenin clinical translation healing improved innovation male men muscle physiology muscle regeneration muscle strength novel novel diagnostics novel strategies novel therapeutics older men older women patient population prevent programs public health relevance tool urinary

项目摘要

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.

描述（由申请人提供）：我们的提案侧重于新颖的药理学干预策略，以改善患有尿失禁的老年退伍军人群体的生活质量。随着老年退伍军人人口的迅速增长，这将成为退伍军人管理局医疗系统的重大健康负担。尿失禁（UI；不自主漏尿）影响大量男性和女性（>15%），且发病率随着年龄的增长而增加。它是一种严重的医疗疾病，会对人们的生活质量产生不利影响。尿道括约肌和盆底肌肉 (PFM) 在尿失禁机制中发挥着重要作用，这些肌肉与年龄相关的退行性变化被认为是老年人群中 UI 的最常见原因。 PFM（女性）或尿道括约肌（男性）损伤被认为是括约肌复合体功能障碍的重要原因。我们假设括约肌复合体损伤后肌肉再生受损以及晚期衰老过程中观察到的纤维化/肌肉萎缩增加是由一种新的分子途径（Wnt -ß 连环蛋白信号传导）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策略来治疗老年人群中的这种疾病。我们的初步动物（兔子）研究证实了我们的假设，并表明针对 Wnt 信号通路可以减轻括约肌萎缩/纤维化并改善肌肉功能。我们的具体目标是： 1) 确定 Wnt/β-连环蛋白信号通路在新肌纤维再生、纤维化/和 EAS 肌肉功能及其结构在手术损伤后的形成中的作用； 2) 评估衰老对尿道/PFM肌肉功能的影响，确定Wnt信号通路在年龄相关的肌肉功能退行性改变中的作用；（3）。 (A) 使用新型 MR 扩散张量成像 (DTI) 评估接受前列腺切除术的男性在自发愈合过程之前和期间的尿道括约肌复合体的肌结构； (B) 将失禁恢复的时间过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理将能够确定新的治疗策略，以预防与年龄相关的括约肌退化，并改善老年退伍军人群体的自控能力。该提案有望解决理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，并提供一种新型多功能药剂来预防/管理这种影响许多老年男性和女性生活质量的疾病。我们的提案具有创新性，包括新颖的概念（与损伤相关的括约肌功能障碍是由于肌肉再生紊乱、胶原蛋白沉积过多和肌纤维方向紊乱造成的。过度纤维化是由 Wnt 信号传导增加引起的）、新颖的方法（用 Wnt 信号拮抗剂进行药物干预以改善括约肌功能）和新颖的工具（新颖的高清测压法和 MR-DTI 来研究括约肌）再生肌肉的功能和肌肉结构）。总之，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（W nt 拮抗剂的潜在用途），以最大限度地提高老龄退伍军人群体的功能恢复（尿失禁功能）。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Novel Endoluminal Ultrasound Imaging Technique to Determine Urethral Luminal Cross-Sectional Area.

一种确定尿道管腔横截面积的新型腔内超声成像技术。

DOI：
10.1089/end.2018.0554
发表时间：
2018
期刊：
Journal of endourology
影响因子：
2.7
作者：
Bhargava,Raag;Yu,Hosong;Chilukuri,AbinavT;Kim,Jaesoo;Yuk,Seung-Mo;Lee,Seung-Ryeol;Fuller,ThomasW;Buckley,JillC;Bhargava,Valmik;Rajasekaran,MahadevanRaj
通讯作者：
Rajasekaran,MahadevanRaj

Preclinical applications of high-definition manometry system to investigate pelvic floor muscle contribution to continence mechanisms in a rabbit model.

高清测压系统的临床前应用研究盆底肌肉对兔子模型失禁机制的贡献。