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（由申请人提供）：炎症性肠病患者经常出现膀胱过度活动症，反映感觉过敏；然而，这种临床综合征的机制尚不清楚。我们实验室和其他实验室的研究表明，结肠炎动物模型表现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）和脊髓初级传入神经水平的神经元相互作用可能在结肠至膀胱过敏中发挥作用。本提案的目的是研究神经营养素作为初级传入交叉激活和超敏性介质在大鼠结肠内滴注三硝基苯磺酸 (TNBS) 诱导的结肠炎后结肠至膀胱敏化中的作用。我们的假设是，结肠炎诱导 DRG 传入神经元之间的神经元相互作用，部分是通过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来启动的。这导致结肠传入神经元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 的表达增加。 BDNF/TrkB 和相关信号通路的增加导致膀胱传入神经元中兴奋性神经递质降钙素基因相关肽 (CGRP) 的诱导； BDNF 和 CGRP 反过来导致通道表达改变，部分介导膀胱传入神经元的超敏反应。具体目标是：1）表征结肠传入神经元中的 NGF/TrkA 和信号通路，这些神经元导致结肠炎后腰骶部 DRG 中 BDNF 的表达； 2) BDNF/TrkB 的表征以及导致结肠炎后 DRG 膀胱传入神经元中 CGRP 和离子通道表达的信号通路； 3) 通过膀胱传入神经元的通道活动以及结肠炎后的膀胱排尿参数来测量 BDNF 和 CGRP 对膀胱过敏调节的影响。实验将采用系统方法进行，包括通过直接测量信号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素、神经肽及其受体和信号通路的表达。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该综合征的理解，并提出更好的控制或治疗方法。