Neurotrophins and Neuropeptides in Colon and Bladder Hypersensitivity

结肠和膀胱过敏中的神经营养素和神经肽

• 批准号: 8257168
• 负责人: Liya Qiao
• 金额: $ 29.21万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257168
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Afferent Neurons; Afferent Pathways; Affinity; Animal Model; Antibodies; Attenuated; Bladder; Bladder Control; Brain-Derived Neurotrophic Factor; C Fiber; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Calcium; Clinical; Colitis; Colon; Coupled; Distal; Enzyme-Linked Immunosorbent Assay; Esthesia; Genetic Transcription; Human; Hypersensitivity; Immune Sera; Inflammation; Inflammatory Bowel Diseases; Intracolonic; Investigation; Ion Channel; Label; Laboratories; Lead; MAPK7 gene; MEKs; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nerve Growth Factors; Neuraxis; Neurogenic Bladder; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 1; Organ; Overactive Bladder; Pathway interactions; Patients; Peripheral; Phosphatidylinositols; Phosphorylation; Play; Polymerase Chain Reaction; Potassium; Process; Rat-1; Rattus; Receptor Signaling; Regulation; Research Proposals; Resistance; Role; Sensory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sodium; Spinal Cord; Spinal Ganglia; Study models; Sulfonic Acids; Syndrome; System; Time; Up-Regulation; Urination; Urodynamics; Visceral; Western Blotting; Work; afferent nerve; experience; inhibitor/antagonist; irritation; neurochemistry; neuronal excitability; neurotrophic factor; nitrobenzene; patch clamp; relating to nervous system; research study

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease often experience overactive bladder reflecting sensory hypersensitivity; however the mechanism underlying this clinical syndrome is not clear. Studies from our laboratory and others indicate that animal models of colitis demonstrate a similar cross-sensitization that leads to neurogenic bladder overactivity. Neuronal interaction at the level of primary afferents in dorsal root ganglia (DRG) and spinal cord likely plays a role in the colon-to-bladder hypersensitivity. The objective of this proposal is to investigate the role of neurotrophins as mediators of primary afferent cross-activation and hypersensitivity in colon-to-bladder sensitization following colitis induced by intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS) in rat. Our hypothesis is that colitis induces neuronal interaction between afferent neurons in DRG that is initiated, in part, by increases in nerve growth factor (NGF)/TrkA receptor and associated signaling pathways in colonic afferent neurons. This leads to increased expression of brain-derived neurotrophic factor (BDNF) in colonic afferents and increases in BDNF and TrkB in bladder afferent neurons. The increases in BDNF/TrkB and associated signaling pathways lead to subsequent induction of the excitatory neurotransmitter calcitonin gene-related peptide (CGRP) in bladder afferent neurons; BDNF and CGRP, in turn, lead to altered channel expression which mediates in part the hypersensitivity of bladder afferent neurons. The specific aims are: 1) characterization of NGF/TrkA and signaling pathway(s) in colonic afferent neurons that lead to the expression of BDNF in lumbosacral DRG following colitis; 2) characterization of BDNF/TrkB and signaling pathways that lead to the expression of CGRP and ion channel(s) in bladder afferent neurons in DRG following colitis; and 3) characterization of the effects of BDNF and CGRP on the regulation of bladder hypersensitivity as measured by channel activity of bladder afferent neurons as well as bladder micturition parameters following colitis. The experiments will be done with a systematic approach involving measurements of neurotrophins, neuropeptides, and expression of their receptors and signaling pathways by direct measurements of signaling intermediates and use of antagonists, antisera, and selective inhibitors. The investigation of the mechanism underlying neuronal control of bladder and colon function in inflammation will advance understanding of this syndrome as well as suggest approaches for better control or treatment.

描述（由申请方提供）：炎症性肠病患者经常出现膀胱过度活动症，反映感觉超敏反应;然而，该临床综合征的潜在机制尚不清楚。来自我们实验室和其他人的研究表明，结肠炎动物模型显示出类似的交叉致敏作用，导致神经源性膀胱过度活动。背根神经节（DRG）和脊髓中初级传入水平的神经元相互作用可能在结肠-膀胱超敏反应中起作用。本研究的目的是探讨神经营养因子作为初级传入交叉激活和超敏反应介质在结肠-膀胱致敏中的作用，结肠内滴注三硝基苯磺酸（TNBS）诱导大鼠结肠炎。我们的假设是结肠炎诱导DRG中传入神经元之间的神经元相互作用，其部分由结肠传入神经元中神经生长因子（NGF）/TrkA受体和相关信号通路的增加启动。这导致结肠传入神经中脑源性神经营养因子（BDNF）的表达增加，以及膀胱传入神经元中BDNF和TrkB的增加。BDNF/TrkB和相关信号通路的增加导致随后在膀胱传入神经元中诱导兴奋性神经递质降钙素基因相关肽（CGRP）; BDNF和CGRP反过来导致改变的通道表达，其部分介导膀胱传入神经元的超敏性。具体目标是：1）表征结肠炎后导致腰骶DRG中BDNF表达的结肠传入神经元中的NGF/TrkA和信号传导途径;和3）通过膀胱传入神经元的通道活性以及结肠炎后的膀胱排尿参数测量，表征BDNF和CGRP对膀胱超敏性调节的作用。实验将采用系统方法进行，包括通过直接测量信号传导中间体和使用拮抗剂、抗血清和选择性抑制剂来测量神经营养因子、神经肽及其受体和信号传导通路的表达。对炎症中膀胱和结肠功能的神经元控制机制的研究将促进对这种综合征的理解，并提出更好的控制或治疗方法。