Pathogenesis of Detrusor Underactivity and Urinary Retention in the Frail Elderly

描述(申请人提供)：尿失禁在虚弱的老年人中尤其普遍，使人虚弱，费用昂贵，情况复杂。虚弱的老年人有逼尿肌活动不足(DU)的风险，这种情况存在于近三分之二的失禁疗养院居民中。尿毒症影响临床表现，并可能阻碍急性尿潴留、慢性尿潴留、良性前列腺增生症和逼尿肌过度活动的治疗。逼尿肌过动伴收缩功能受损(DHIC)是一种特别常见和具有挑战性的疾病。其临床处理仍然不令人满意，因为抗胆碱能抗痉挛药物可能会恶化保留，而目前的DU治疗是无效的。逼尿肌退行性变、纤维化和轴突变性的存在定义了人类膀胱活检中的DU。我们的目标将通过4个具体目标来实现：目标1.研究尿潴留在促进膀胱肌丢失、纤维化和轴突变性中的作用，重点关注那些可能与其他危险因素共享的途径，从而为DU设计有针对性的干预措施，DU是一种复杂的多因素老年疾病。我们认为，一种被称为巨噬细胞移动抑制因子(MIF)的非典型细胞因子参与了尿潴留促进肌肉丢失、纤维化和轴突变性的途径，这些途径是由于MIF从丰富的尿路上皮细胞中释放出来。目的2.研究雌激素缺乏在膀胱肌丧失、纤维化和轴索变性中的作用，重点探讨可能与其他危险因素共享的途径，从而为治疗DU设计靶向干预措施。DU是一种复杂的多因素老年疾病。我们认为，MIF也参与了卵巢切除促进肌肉丢失、纤维化和轴突变性的途径。目的3.研究衰老对膀胱对尿潴留或卵巢切除的反应能力的影响，重点研究衰老可能与其他危险因素共同存在的途径，从而为针对DU设计针对性的干预措施。DU是一种复杂的多因素老年疾病。目的4.研究衰老对尿路上皮细胞作为生理、炎症和内分泌刺激之间调节接口功能的影响，这些刺激与肌肉丢失、纤维化和轴突变性有关。我们认为，尿路上皮是物理刺激、炎症刺激和内分泌刺激相互作用影响MIF和其他炎症介质合成和释放的调节部位。我们还提出，随着年龄的增长，非上皮性膀胱组织作为MIF的主要来源具有意想不到的重要性，将控制点从尿路上皮细胞转移到别处。

DESCRIPTION (provided by applicant): Urinary incontinence is particularly prevalent, debilitating, costly and complex in the frail elderly. Frail older adults are at risk for detrusor underactivity (DU), a condition present in nearly 2/3 of incontinent nursing home residents. DU influences the clinical presentation and may impede therapy of acute urinary retention, chronic urinary retention, benign prostatic hyperplasia and detrusor overactivity. Detrusor Hyperactivity with Impaired Contractility (DHIC) is especially common and challenging. Its clinical management remains unsatisfactory since anticholinergic antispasmodic medications may worsen retention, while current DU treatments are ineffective. Presence of detrusor muscle degeneration, fibrosis and axonal degeneration defines DU in human bladder biopsies. Our goals will be accomplished via 4 Specific Aims: AIM 1. Examine role of urinary retention in promoting bladder muscle loss, fibrosis and axonal degeneration, focusing on those pathways which may be shared with other risk factors, thus permitting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that an atypical cytokine called MIF (macrophage migration inhibitory factor) is involved in the pathways by which urinary retention promotes muscle loss, fibrosis and axonal degeneration following MIFs release from abundant urothelial stores. AIM 2. Examine role of estrogen depletion in bladder muscle loss, fibrosis and axonal degeneration, focusing on those pathways which may be shared with other risk factors, thus permiting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that MIF is also involved in the pathways by which ovariectomy promotes muscle loss, fibrosis and axonal degeneration. AIM 3. Examine the impact of aging on the ability of the bladder to respond to urinary retention or ovariectomy, focusing on those pathways which aging may share with the other risk factors, thus permitting the design of targeted interventions for DU, a complex multifactorial condition in the frail elderly. We propose that aging enhances the bladder's vulnerability to develop muscle loss, fibrosis and axonal up AIM 4. Examine impact of aging on the ability of the urothelium to function as a regulatory interface between physical, inflammatory and endocrine stimuli involved in muscle loss, fibrosis and axonal degeneration. We propose that the urothelium represents a regulatory site where physical, inflammatory and endocrine stimuli interact in influencing the synthesis and release of MIF and other inflammatory mediators. We also propose that with aging, non-epithelial bladder tissues assume an unexpected importance as a major source of MIF, shifting the locus of control away from urothelial cells.