Neurotrophic Mechanisms in LUT Plasticity with Cystitis

膀胱炎 LUT 可塑性的神经营养机制

• 批准号: 6709614
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 30.15万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709614
• 关键词: adenylate cyclase; afferent nerve; chronic pain; interstitial cystitis; laboratory mouse; laboratory rat; neuropeptide receptor; neuropeptides; neurotrophic factors; protein localization; protein tyrosine kinase; receptor expression; reflex; smooth muscle; spinal ganglion; urinary bladder epithelium; urination

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.

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，其特征在于尿频，紧急，腹膜上和骨盆疼痛。尽管IC的病因和发病机理尚不清楚，但许多理论包括：已经提出了感染，自身免疫性疾病，有毒尿毒剂，膀胱壁壁缺乏以及神经源性原因。垂体腺苷酸环化酶激活多肽（PACAP）在下尿路（LUT）中发挥不同的作用。在膀胱壁上和腹膜丛中已经鉴定出表达PACAP的感觉纤维，在慢性膀胱炎和药理学剂后，排尿反射途径中的PACAP表达在慢性PACAP受体功能后会降低膀胱炎后膀胱过度活动过度。 PACAP表达可以由神经营养蛋白调节。相反，最近的研究还表明，PACAP可以调节神经营养蛋白受体酪氨酸激酶的表达和激活。膀胱炎明显改变了膀胱组织中神经营养蛋白表达的特征。因此，靶器官生长因子水平的变化可能会促进与膀胱炎的排尿途径中的神经化学和功能可塑性。我们工作的总体假设是，IC中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。中心假设是，vipipacap系统是膀胱感觉和功能的突出调节剂，以及炎症引起的神经营养因子的变化和/或神经活性在膀胱中改变了LUT的PACAP/PACAP受体表达，以介导IC中介导的缩影功能。以下三个目标检验了这些假设。 1）。为了表征尿路上皮的PACAP和PACAP受体表达，膀胱平滑肌和膀胱DRG中的膀胱传入细胞； 2）。在正常的排尿反射途径和膀胱炎后建立PACAP和神经营养系统之间的功能关系。 3）。使用PACAP基因敲除小鼠评估PACAP和神经营养蛋白在排尿反射途径中的生理作用。