Effects of Inflammation in a Mouse Model of Interstital Cystitis

炎症对间质性膀胱炎小鼠模型的影响

• 批准号: 8256405
• 负责人: Jennifer J DeBerry
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-30 至 2013-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256405
• 关键词: Acute; Afferent Neurons; Animals; Area; Basic Science; Binding; Bladder; Bladder Diseases; Bladder Dysfunction; Cells; Chronic; Chronic Disease; Clinical Sciences; Cystitis; Development; Esthesia; Exhibits; Functional disorder; Future; GDNF gene; Gene Expression; Genetic Transcription; Growth Factor; Growth Factor Receptors; Hypersensitivity; Immersion Investigative Technique; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Ion Channel; Knowledge; Label; Membrane; Messenger RNA; Methods; Molecular; Neurons; Neuropathy; Nociception; Organ; Outcome; Pain; Pathogenesis; Pelvis; Phenotype; Physiological; Physiology; Play; Population; Population Heterogeneity; Potassium Channel; Property; Publishing; Quality of life; Rattus; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Sensory Ganglia; Signal Transduction; Spinal Ganglia; Symptoms; TRPV1 gene; Techniques; Testing; Training Programs; Urologic Diseases; Viscera; Work; base; chronic pain; design; immunocytochemistry; insight; mouse model; nerve supply; neurochemistry; neuronal excitability; neurotrophic factor; painful bladder syndrome; patch clamp; receptor; research study; response; spine bone structure; voltage

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is an inflammatory chronic bladder disorder characterized by suprapubic pain and bladder dysfunction. Although the pathogenesis of IC is unclear, there is substantial evidence from clinical and basic science studies that growth factor signaling mechanisms may play a role. Growth factors made by the inflamed bladder can potentiate sensory transduction in primary sensory afferents by acting on membrane receptors and ion channels, including K+ channels. These channels are attractive targets for pharmacological modulation of bladder pain and hypersensitivity in IC. Pelvic viscera, including the bladder, receive dual innervation from sensory ganglia arising from two distinct vertebral levels (T13-L2 [TL] and L5-S1 [LS]), and it is thought these populations contribute to different aspects of organ function and sensation. A lack of knowledge regarding how these subpopulations respond to different growth factors or are differentially modulated as a result of changes in K+ curents hampers a complete understanding of bladder afferent function and dysfunction. The hypothesis directing this work is that bladder inflammation induces alterations in the transcriptional expression of Kv channels and biophysical properties of bladder sensory neurons in distinct subpopulations sensory neurons, differentiated in part on their growth factor sensitivity and anatomical distribution. We further propose that these changes may become permanent and result in hyperexcitability contributing to persistent bladder pain. This hypothesis will be tested in a mouse model of IC using molecular and physiological techniques. The experiments are designed such that regardless of the outcome, we will have a better understanding of the phenotype of distinct subpopulations of bladder afferents and potential changes that occur in those afferents in response to inflammation, as well as increased insight into the role played by the primary sensory neuron in the development of persistent bladder pain and dysfunction. PUBLIC HEALTH RELEVANCE: Interstitial cystitis (IC) is a chronic, debilitating urological disorder that is difficult to treat and significantly reduces quality of life. Pain and altered blader function are the most troubling symptoms. The broad objective of this research is to examine the cellular and molecular mechanisms underlying urinary bladder nociception and hypersensitivity. This research will lay a firm groundwork for future studies aimed at developing well-informed and successful pharmacological interventions with a high degree of translational significance for the management of IC pain.

描述（由申请方提供）：间质性膀胱炎（IC）是一种炎症性慢性膀胱疾病，其特征为耻骨上疼痛和膀胱功能障碍。虽然IC的发病机制尚不清楚，但临床和基础科学研究的大量证据表明，生长因子信号传导机制可能发挥作用。由发炎膀胱产生的生长因子可通过作用于膜受体和离子通道（包括K+通道）来增强初级感觉传入中的感觉转导。这些通道是IC中膀胱疼痛和超敏反应的药理学调节的有吸引力的靶点。盆腔脏器（包括膀胱）接受来自两个不同椎体水平（T13-L2 [TL]和L5-S1 [LS]）的感觉神经节的双重神经支配，并且认为这些群体有助于器官功能和感觉的不同方面。缺乏知识，这些亚群如何响应不同的生长因子或差异调制的K+电流的变化的结果阻碍了膀胱传入功能和功能障碍的完整理解。指导这项工作的假设是，膀胱炎症诱导Kv通道的转录表达和膀胱感觉神经元的生物物理特性在不同的亚群感觉神经元中的改变，部分分化在它们的生长因子敏感性和解剖分布上。我们进一步提出，这些变化可能成为永久性的，并导致过度兴奋，导致持续性膀胱疼痛。将使用分子和生理学技术在IC小鼠模型中测试该假设。这些实验的设计使得无论结果如何，我们都将更好地了解膀胱传入神经的不同亚群的表型以及这些传入神经对炎症反应的潜在变化，以及对初级感觉神经元在持续性膀胱疼痛和功能障碍的发展中所起作用的深入了解。 公共卫生相关性：间质性膀胱炎（IC）是一种慢性、使人衰弱的泌尿系统疾病，难以治疗并显著降低生活质量。疼痛和膀胱功能改变是最令人不安的症状。本研究的主要目的是研究膀胱伤害性感受和超敏反应的细胞和分子机制。这项研究将为未来的研究奠定坚实的基础，旨在开发充分知情和成功的药理学干预措施，具有高度的翻译意义的IC疼痛的管理。