Pathogenesis of Detrusor Underactivity and Urinary Retention in the Frail Elderly

描述（由申请人提供）：尿失禁在体弱的老年人中特别普遍，使人虚弱，昂贵且复杂。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2/3的失禁疗养院居民中。DU影响急性尿潴留、慢性尿潴留、良性前列腺增生和逼尿肌过度活动症的临床表现，并可能妨碍治疗。逼尿肌功能亢进伴收缩力受损（DHIC）尤其常见且具有挑战性。其临床管理仍然不能令人满意，因为抗胆碱能解痉药物可能会恶化保留，而目前的DU治疗无效。逼尿肌变性、纤维化和轴突变性的存在定义了人类膀胱活检中的DU。我们的目标将通过四个具体目标实现：目标1。检查尿潴留在促进膀胱肌肉损失，纤维化和轴突变性中的作用，重点关注可能与其他风险因素共享的途径，从而允许设计针对DU的有针对性的干预措施，DU是体弱老年人中的一种复杂的多因素疾病。我们提出，一种非典型的细胞因子称为MIF（巨噬细胞迁移抑制因子）参与尿潴留促进肌肉损失，纤维化和轴突变性的途径后，从丰富的尿路上皮商店释放MIF。AIM 2.检查雌激素耗竭在膀胱肌肉损失，纤维化和轴突变性中的作用，重点关注可能与其他风险因素共享的途径，从而为DU（体弱老年人中的复杂多因素疾病）设计有针对性的干预措施。我们认为MIF也参与了卵巢切除促进肌肉损失、纤维化和轴突变性的途径。AIM 3.检查老化对膀胱应对尿潴留或卵巢切除术的能力的影响，重点关注老化可能与其他风险因素共享的途径，从而允许设计针对DU的有针对性的干预措施，DU是体弱老年人的复杂多因素条件。我们认为，老化增强了膀胱的脆弱性，发展肌肉损失，纤维化和轴突向上AIM 4。检查老化对尿道功能的影响，作为肌肉损失，纤维化和轴突变性中涉及的物理，炎症和内分泌刺激之间的调节界面。我们认为，尿路上皮是一个调节部位，物理，炎症和内分泌刺激相互作用，影响MIF和其他炎症介质的合成和释放。我们还提出，随着年龄的增长，非上皮膀胱组织承担了一个意想不到的重要性，作为一个主要来源的MIF，转移控制点远离尿路上皮细胞。

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.