Neurotrophic Mechanisms in LUT Plasticity with Cystitis

描述(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，以尿频、尿急、耻骨上和盆腔疼痛为特征。尽管IC的病因和发病机制尚不清楚，但已有多种学说提出，包括：感染、自身免疫紊乱、中毒性尿路感染、膀胱壁衬里缺陷和神经源性原因。垂体腺苷环化酶激活多肽(PACAP)在下尿路(LUT)中发挥着广泛而广泛的作用。在膀胱壁和膀胱上皮下神经丛中已发现PACAP的表达，慢性膀胱炎后排尿反射通路中PACAP的表达上调，阻断PACAP受体功能的药物可减少膀胱炎后的膀胱过度活动。PACAP的表达可以受神经营养因子的调节；相反，最近的研究也表明PACAP可能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素的表达。因此，靶器官生长因子水平的变化可能推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、尿路上皮和感觉生理学的改变。中心假说是VIPACAP系统是膀胱感觉和功能的重要调节器，炎症引起的神经营养因子和/或膀胱神经活动的变化改变了LUT中PACAP/PACAP受体的表达，从而介导了IC排尿功能的改变。以下三个目标验证了这些假设。1)。研究脊髓背根节尿路上皮、膀胱平滑肌和膀胱传入细胞中PACAP及其受体的表达；建立正常排尿反射通路和膀胱炎后PACAP与神经营养因子系统的功能关系。用PACAP基因敲除小鼠评价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.