TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction

摘要：儿童应激性膀胱功能障碍(SIBD)可表现为膀胱过度活动(OAB)或 膀胱活动不足/膀胱排空不全(UAB)。膀胱功能障碍在医学上、社会上、 在情感和行为方面；然而，治疗选择有限，而且往往无效。最近，我们有 成人病理生理学中涉及的瞬时受体电位香草素家族1型(TRPV1)通道 OAB，但它们在SIBD中的角色尚不清楚。处于社会压力下的幼鼠会出现OAB或UAB， 这取决于压力的强度和持续时间。当社会压力导致过度活动时，TRPV1介导 膀胱传入活动增加，这在非应激小鼠中是完全没有的。当社会压力导致 活动不足，传入活动没有变化，但膀胱明显重塑和失代偿。 有趣的是，无论社交活动的强度或持续时间如何，TRPV1-KO小鼠都没有发生SIBD或任何类型的SIBD 压力。因此，我们假设SIBD是进行性的，从而(1)应激增加TRPV1依赖 传入神经活动，导致膀胱过度活动；(2)这些异常信号传递到中枢神经系统 (3)中枢神经系统(CNS)结合膀胱过度活动本身可导致膀胱重塑； 膀胱顺应性、传入流出和肌肉收缩，导致活动不足并最终排尿 留存。这项建议将通过我们独特的 应激诱导的膀胱功能障碍的小鼠模型，与儿童膀胱病理模型密切相关。在这 ，我们将调查社会压力的持续时间/强度如何导致膀胱功能障碍，并确定 TRPV1通道在SIBD进展中的作用我们将部署广泛的技术(组织学、 荧光原位杂交、体外传入神经记录、成像、膀胱测压、意识排尿 行为)和一系列转基因和基因敲除小鼠模型，以探索SIBD和 确定TRPV1通道如何影响膀胱功能。关于膀胱过度活动和活动不足的想法 由异常的TRPV1发展而来的通道敏化简化了我们对应激如何导致膀胱的理解 功能障碍，并可能导致有效的治疗这种虚弱的情况。

SUMMARY: Stress-induced bladder dysfunction (SIBD) in children can manifest as overactive bladder (OAB) or underactive bladder/incomplete bladder emptying (UAB). Bladder dysfunction affects children medically, socially, emotionally and behaviorally; yet treatment options are limited and often ineffective. Recently, we have implicated transient receptor potential vanilloid family type1 (TRPV1) channels in the pathophysiology of adult OAB, but their roles in SIBD are unknown. Juvenile mice subjected to social stress developed OAB or UAB, depending on the intensity and duration of the stress. When social stress caused overactivity, TRPV1-mediated bladder afferent activity increased that was wholly absent in unstressed mice. When social stress caused underactivity, afferent activity was unchanged, but bladders were significantly remodeled and decompensated. Interestingly, TRPV1-KO mice developed no SIBD or any kind, regardless of the intensity or duration of social stress. Thus, Thus, we hypothesize that SIBD is progressive, such that (1) stress increases TRPV1-dependent afferent nerve activity, leading to bladder overactivity; (2) these aberrant signals to the central nervous system (CNS) coupled with bladder overactivity itself result in bladder remodeling; and (3) this remodeling decreases bladder compliance, afferent outflow and muscle contractility, leading to underactivity and ultimately urinary retention. This proposal will mechanistically investigate the onset and progression of SIBD through our unique murine model of stress-induced bladder dysfunction, which closely models pediatric bladder pathology. In this proposal, we will investigate how the duration/intensity of social stress causes bladder dysfunction and determine the role TRPV1 channels play in the progression of SIBD. We will deploy a wide array of techniques (histology, fluorescent in situ hybridization, ex vivo afferent nerve recordings, imaging, cystometry, conscious voiding behavior) and an array of transgenic and knockout mouse models to explore the pathophysiology of SIBD and determine how TRPV1 channels affect bladder function. The idea that both bladder overactivity and underactivity develop from aberrant TRPV1 channel sensitization simplifies our understanding of how stress causes bladder dysfunction and may lead to effective treatments for this debilitating condition.