Neurovascular and Behavorial Response to Cystitis

描述(申请人提供)：间质性膀胱炎(IC)是一种病因不明的疾病，主要导致耻骨上疼痛增加和排尿频率增加。尽管IC通常出现在尿路感染(急性或反复)之后，但尿路感染对膀胱神经、血管和功能的急性和慢性影响尚未得到很好的表征。大多数动物模型中炎性膀胱炎的研究都是利用化学诱导的膀胱炎模型，并集中在急性影响上。迫切需要将对化学性膀胱炎的观察扩大到细菌性膀胱炎的影响，并确定急性和慢性感染性膀胱炎的长期影响。这项拟议的研究将解决这样的假设，即反复尿路感染导致膀胱神经、血管和功能的持续变化，这些变化在感染明显缓解后导致IC的症状。我们还将讨论这样的推论，即这些变化可能被全身应用CYP引起的长期化学性膀胱炎所模拟，并且小鼠对持久感染的敏感性在不同品系的小鼠之间存在差异，炎性膀胱炎对膀胱神经、血管和功能的影响不同。这项拟议的研究将使用一种综合的实验方法和新的成像技术来表征对膀胱炎(急性和慢性)的细胞、组织学、神经和行为反应，并确定在去除启动刺激后变化是否持续。这项研究将调查针对常见临床问题而发生的变化的持久性，并阐明“简单的UTR”可能在复杂的IC临床面貌下的膀胱生理和功能、神经调节、疼痛感知和行为方面产生一连串变化的方式。这一系列研究的长期计划是将拟议研究中产生的信息与未来对不同品系小鼠膀胱炎易感性差异的遗传基础调查联系起来，以及这与人类对UTI影响的敏感性以及对不明原因的痛性膀胱疾病(如IC)的发生的差异有何关系。

DESCRIPTION (provided by applicant): Interstitial Cystitis (IC) is a disorder of uncertain etiology that primarily results in increased supra-pubic pain and increased voiding frequency. Although IC often appears to develop in the wake of urinary tract infection (acute or repeated), the acute and chronic effects of urinary tract infection on bladder innervation, vasculature, and function have not been well characterized. Most studies of inflammatory cystitis in animal models have utilized chemically induced models of cystitis and focused on acute effects. There is a critical need to extend observations made on chemically induced cystitis to the effects of bacterial cystitis and to characterize the long-term effects of acute and chronic infectious cystitis. The proposed research will address the hypothesis that repeated urinary tract infection results in persistent changes in bladder innervation, vasculature, and function that contribute to symptoms of IC after the infection is apparently resolved. We will also address the corollary hypotheses that these changes may be mimicked by prolonged chemical cystitis induced by systemic administration of CYP and that susceptibility of mice to the durable the effects of inflammatory cystitis on bladder innervation, vasculature, and function vary among different strains of mice. The proposed research will use an integrated experimental approach and novel imaging techniques to characterize the cellular, histological, neurological, and behavioral response to bladder inflammation (acute and chronic) and determine whether changes persist after removal of the initiating stimulus. This research will investigate the durability of changes that occur in response to a common clinical problem and elucidate the ways in which a "simple UTr' may create a cascade of changes in the bladder physiology and function, neuroregulation, pain perception and behavior that underlie the complex clinical face of IC. The long range plan for this line of research is to link the information generated in the proposed study to future investigations into the genetic basis for variations in susceptibility to cystitis among strains of mice and how this relates to variability among humans regarding sensitivity to the effects of UTI and the occurrence of painful bladder disorders of uncertain etiology, such as IC.