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（由申请人提供）：间质性膀胱炎（IC）是一种炎症性慢性膀胱疾病，其特征是上肾上腺疼痛和膀胱功能障碍。尽管IC的发病机理尚不清楚，但从临床和基础科学研究中有大量证据表明生长因子信号传导机制可能起作用。发炎的膀胱产生的生长因子可以通过在包括K+通道在内的膜受体和离子通道（包括K+通道）上作用，从而增强一级感觉传入的感觉转导。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标。包括膀胱在内的骨盆内脏，从两个不同的椎骨水平（T13-L2 [TL]和L5-S1 [LS]）引起的感觉神经节接收双重神经支配，并认为这些人群有助于器官功能和感觉的不同方面。缺乏有关这些亚群如何响应不同生长因子的知识，或者由于K+级别的变化而受到差异调制，这阻碍了人们对膀胱传入功能和功能障碍的完全了解。指导这项工作的假设是，膀胱炎症引起了不同亚群感觉神经元中膀胱感觉神经元的KV通道和生物物理特性的转录表达的改变，部分地取决于其生长因子敏感性和解剖学分布。我们进一步建议，这些变化可能成为永久性的，并导致过度刺激导致膀胱疼痛。该假设将在使用分子和生理技术的IC的小鼠模型中进行检验。实验的设计使得无论结果如何，我们都将更好地理解膀胱传入的不同亚群的表型，以及这些传入中响应炎症的那些传入中发生的潜在变化，以及对持续性膀胱疼痛和功能障碍发育中主要感觉神经元在发育中起作用的作用。 公共卫生相关性：间质性膀胱炎（IC）是一种慢性，令人衰弱的泌尿科障碍，难以治疗并大大降低生活质量。疼痛和膀胱功能改变是最令人不安的症状。这项研究的广泛目的是检查泌尿膀胱伤伤心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，旨在开发具有良好信息和成功的药理干预措施，对IC疼痛的管理具有高度的翻译意义。