Neurovascular and Behavorial Response to Cystitis

描述（由申请人提供）：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。虽然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支配、脉管系统和功能的急性和慢性影响尚未得到很好的表征。大多数炎性膀胱炎动物模型的研究都是利用化学诱导的膀胱炎模型，并集中在急性效应上。目前迫切需要将化学诱导膀胱炎的观察结果扩展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。本研究将解决反复尿路感染导致膀胱神经支配、脉管系统和功能持续改变的假设，这些变化有助于在感染明显消退后出现IC症状。我们还将讨论一些推论假设，即这些变化可能是由全身注射CYP引起的长期化学膀胱炎所模拟的，并且小鼠对炎症性膀胱炎对膀胱神经支配、脉管系统和功能的持久影响的易感性在不同品系的小鼠中有所不同。拟议的研究将使用综合实验方法和新的成像技术来表征膀胱炎症（急性和慢性）的细胞、组织学、神经学和行为反应，并确定去除初始刺激后这些变化是否持续。这项研究将调查对常见临床问题的反应所发生的变化的持久性，并阐明“简单的尿路反应”可能在膀胱生理和功能、神经调节、这条研究路线的长期计划是将拟议研究中产生的信息与未来的研究联系起来，研究小鼠对膀胱炎易感性变异的遗传基础，以及这与人类对尿路感染的敏感性和病因不确定的膀胱疼痛疾病（如IC）的发生的变异性之间的关系。

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.