Neurotrophic Mechanisms in LUT Plasticity with Cystitis

描述（由申请人提供）：间质性膀胱炎（IC）是一种慢性炎症性膀胱疾病综合征，其特征为尿频、尿急、耻骨上和盆腔疼痛。虽然IC的病因和发病机制尚不清楚，但已提出了许多理论，包括感染、自身免疫性疾病、毒性泌尿制剂、膀胱壁衬里缺陷和神经源性原因。垂体腺苷酸环化酶激活多肽（PACAP）在下尿路（LUT）中发挥着多种普遍作用。已在膀胱壁和上皮下神经丛中鉴定出表达PACAP的感觉纤维，慢性膀胱炎后排尿反射通路中的PACAP表达上调，阻断PACAP受体功能的药理学药物可减少膀胱炎后的膀胱过度活动。PACAP的表达可受神经营养因子的调节;相反，最近的研究也表明PACAP可调节神经营养因子受体酪氨酸激酶的表达和激活。膀胱炎显著改变了膀胱组织中神经营养因子的表达。因此，靶器官生长因子水平的变化可能会驱动膀胱炎排尿途径的神经化学和功能可塑性。我们工作的总体假设是，IC的疼痛和排尿功能障碍涉及膀胱平滑肌、尿道刺激和感觉生理学的改变。中心假设是VIPIPACAP系统是膀胱感觉和功能的重要调节剂，并且炎症诱导的神经营养因子和/或膀胱中产生的神经活性的变化改变LUT中的PACAP/PACAP受体表达以介导IC中排尿功能的改变。以下三个目标验证了这些假设。1）。研究PACAP及其受体在腰骶背根神经节膀胱、膀胱平滑肌和膀胱传入细胞中的表达。目的探讨PACAP与神经营养因子系统在正常排尿反射通路及膀胱炎后的功能关系。3）。利用PACAP基因敲除小鼠研究PACAP和神经营养因子在排尿反射通路中的生理作用。

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a chronic inflammatory bladder disease syndrome characterized by urinary frequency, urgency, suprapubic and pelvic pain. Although the etiology and pathogenesis of IC are unknown, numerous theories including; infection, autoimmune disorder, toxic urinary agents, deficiency in bladder wall lining and neurogenic causes have been proposed. Pituitary adenylate cyclase activating polypeptide (PACAP) exerts diverse and prevalent roles in the lower urinary tract (LUT). Sensory fibers expressing PACAP have been identified in the bladder wall and in suburothelial plexuses, PACAP expression in the micturition reflex pathway is upregulated following chronic cystitis and pharmacological agents that block PACAP receptor function reduce bladder overactivity after cystitis. PACAP expression can be regulated by neurotrophins; conversely, recent studies have also suggested that PACAP may regulate neurotrophin receptor tyrosine kinase expression and activation. Cystitis markedly alters the profile of neurotrophin expression in bladder tissues. Thus, the resulting changes in target organ growth factor levels may drive the neurochemical and functional plasticity in the micturition pathway with cystitis. The overall hypothesis for our work is that pain and micturition dysfunction in IC involves an alteration in bladder smooth muscle, urothelium and sensory physiology. The central hypothesis is that the VIPIPACAP system is a prominent modulator of bladder sensation and function and the inflammation-induced changes in neurotrophic factors and/or neural activity arising in the bladder alter PACAP/PACAP receptor expression in LUT to mediate altered micturition function in IC. The following three aims test these hypotheses. 1). To characterize PACAP and PACAP receptor expression in urothelium, bladder smooth muscle and bladder afferent cells in the lumbosacral DRG; 2). To establish the functional relationships between PACAP and neurotrophin systems in the normal micturition reflex pathway and after cystitis.; 3). To evaluate the physiological roles of PACAP and neurotrophins in the micturition reflex pathway using PACAP knockout mice.