TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction

总结 儿童应激性膀胱功能障碍（SIBD）可表现为膀胱过度活动症（OAB）或活动不足 膀胱/膀胱排空不全（UAB）。膀胱功能障碍会影响儿童的医疗，社会， 情绪和行为;然而，治疗选择有限，而且往往无效。最近我们 瞬时受体电位香草酸家族1型（TRPV 1）通道与成人脑缺血的病理生理学有关 OAB，但他们在SIBD中的作用是未知的。受到社会压力的幼年小鼠发展为OAB或UAB， 这取决于压力的强度和持续时间。当社会压力引起过度活跃时，TRPV 1介导的 膀胱传入活动增加，这在未应激的小鼠中完全不存在。当社会压力导致 活动不足，传入活动没有变化，但膀胱显著重塑和失代偿。 有趣的是，TRPV 1-KO小鼠没有发生SIBD或任何类型的SIBD，无论社交活动的强度或持续时间如何。 应力因此，我们假设SIBD是进行性的，例如：（1）应激增加TRPV 1依赖性 传入神经活动，导致膀胱过度活动;（2）这些异常信号到中枢神经系统 (CNS)再加上膀胱过度活动本身导致膀胱重塑;和（3）这种重塑减少 膀胱顺应性、传入流出和肌肉收缩性，导致活动不足，并最终导致排尿困难。 潴留该提案将通过我们独特的方法， 应激诱导的膀胱功能障碍的鼠模型，其密切模拟儿科膀胱病理学。在这 建议，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， 确定TRPV 1通道在SIBD进展中的作用。我们会使用各种技术 （组织学，荧光原位杂交，离体传入神经记录，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来探索SIBD的病理生理学 并确定TRPV 1通道如何影响膀胱功能。膀胱过度活动和 TRPV 1通道敏感性异常导致的活动不足简化了我们对压力如何 导致膀胱功能障碍，并可能导致有效的治疗这种衰弱的条件。

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.