Neurotrophic Mechanisms in LUT Plasticity with Cystitis

膀胱炎 LUT 可塑性的神经营养机制

• 批准号: 7278299
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 27.11万
• 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/7278299
• 关键词: Afferent Neurons; Animals; Autoimmune Diseases; Bladder; Bladder Control; Bladder Diseases; Bladder Tissue; Bladder Urothelium; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Chemicals; Chronic; Chronic Cystitis; Cyclophosphamide; Cystitis; Esthesia; Etiology; Exhibits; Fiber; Figs - dietary; Functional disorder; GDNF gene; Ganglia; Growth Factor; Increased frequency of micturition; Infection; Inflammation; Inflammatory; Interneurons; Interstitial Cystitis; Knockout Mice; Lower urinary tract; Mediating; Membrane; Micturition Reflex; Mus; Myxoid cyst; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Growth Factor Receptors; Neurons; Neuropeptides; Organ; PACAPR-1 protein; Pain; Pathogenesis; Pathway interactions; Pattern; Pelvic Pain; Pelvis; Peptides; Physiological; Pontine structure; Population; Process; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Reflex action; Regulation; Relative (related person); Role; Sensory; Sensory Physiology; Signal Transduction; Site; Smooth Muscle; Special Populations Networks; Spinal Cord; Spinal Ganglia; Synapses; Syndrome; System; Testing; Time; Urination; Urothelium; Work; autocrine; electrical property; insight; iodonitrotetrazolium; irritation; neurochemistry; neurotrophic factor; paracrine; pituitary adenylate cyclase activating polypeptide; receptor; receptor coupling; receptor expression; receptor function; relating to nervous system; research study; theories; trafficking; urinary

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）是一种慢性炎性膀胱疾病综合征，以尿频、尿急、耻骨上和骨盆疼痛为特征。虽然IC的病因和发病机制尚不清楚，但许多理论包括；感染，自身免疫性疾病，尿毒性药物，膀胱壁缺乏和神经源性原因已被提出。垂体腺苷酸环化酶激活多肽（PACAP）在下尿路（LUT）中发挥着多种多样的普遍作用。在膀胱壁和上皮下神经丛中发现了表达PACAP的感觉纤维，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膀胱过度活动。神经营养因子可调节PACAP的表达；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。膀胱炎显著改变膀胱组织中神经营养因子的表达谱。因此，靶器官生长因子水平的改变可能驱动膀胱炎患者排尿通路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的改变。核心假设是VIPIPACAP系统是膀胱感觉和功能的重要调节剂，炎症诱导的膀胱神经营养因子和/或神经活动的变化会改变LUT中PACAP/PACAP受体的表达，从而介导IC中排尿功能的改变。以下三个目的验证这些假设。1）. 探讨PACAP及PACAP受体在腰骶DRG尿路上皮、膀胱平滑肌和膀胱传入细胞中的表达；2）. 探讨PACAP与神经营养因子系统在膀胱炎后及正常排尿反射通路中的功能关系；3）. 以PACAP基因敲除小鼠为实验对象，探讨PACAP基因和神经营养因子在排尿反射通路中的生理作用。