Effects of Inflammation in a Mouse Model of Interstital Cystitis

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，生长因子信号机制可能起作用。发炎膀胱产生的生长因子可以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的感觉传导。这些通道是IC患者膀胱疼痛和超敏反应药理调节的重要靶点。包括膀胱在内的盆腔脏器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，人们认为这些群体参与器官功能和感觉的不同方面。由于缺乏对这些亚群如何对不同生长因子作出反应或由于K+电流的变化而受到差异调节的了解，阻碍了对膀胱传入功能和功能障碍的全面了解。指导这项工作的假设是，膀胱炎症诱导了不同亚群感觉神经元中Kv通道转录表达和膀胱感觉神经元生物物理特性的改变，这些改变在一定程度上取决于它们的生长因子敏感性和解剖分布。我们进一步提出，这些变化可能成为永久性的，并导致过度兴奋性，从而导致持续的膀胱疼痛。这一假设将在小鼠IC模型中使用分子和生理技术进行验证。无论结果如何，我们都将更好地了解膀胱传入神经不同亚群的表型，以及这些传入神经在炎症反应中发生的潜在变化，并加深对初级感觉神经元在持续性膀胱疼痛和功能障碍发展中所起作用的了解。

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.