Contribution of Stress Induced Autonomic and Urothelial Dysregulation to IC/BPS

间质性膀胱炎/膀胱痛综合征(IC/BPS)是一种与尿路相关的慢性疼痛状态。 没有确凿的病因和有效的治疗方法的频率和紧迫性。证据支持 情绪压力在全身性疼痛综合征的恶化(和可能的发展)中的作用 作为IC/BPS以及排尿障碍。MAPP(多学科)最近对一例患者队列的分析 研究骨盆疼痛的方法)网络证实了患有骨盆疼痛的个体之间的显著差异 IC/BPS和健康对照组的心理社会变量以及当前和终身压力。尽管潜在的 压力对疼痛影响的调节机制尚不清楚，最近的证据表明 IC/BPS的慢性应激和膀胱功能障碍可能与自主神经(肾上腺素能)失调有关 影响伤害性信号。我们的初步数据为压力诱导的自主神经提供了证据 外周靶点和线粒体功能的调节可能在膀胱痛中发挥作用。已被占用 总而言之，我们的总体假设是，慢性应激导致自主神经和线粒体 调节失调并导致影响排尿和疼痛的尿路上皮神经信号的变化 行为。我们的研究团队将使用多学科方法，包括分子生物学、测量 应用线粒体生物能量学、电生理学和成像技术研究心理应激对老年人的影响 验证大鼠慢性饮水回避或AS模型。在目标1中，我们将展示慢性压力增加 肾上腺素能信号导致线粒体功能障碍，从而导致UT的观察到的崩溃 障碍。我们将测量水和尿素的渗透性，并使用形态工具来检查慢性 应激损害尿路上皮(UT)的再生。在目标2中，我们将显示慢性交感神经流出增加。 应激改变UT记忆，通过使用功能分析改变线粒体信号(生物能量学； CA+2成像；线粒体ROS的测量)和分子方法。在目标#3中，我们将展示 慢性应激诱导传入性高兴奋性和脊髓神经胶质细胞激活产生症状 IC/BPS中的等价物。我们将研究膀胱传入神经的分布和活动，并使用基因工具 (设计师受体仅由设计师药物DREADDS激活)，以阻断小胶质细胞的激活和 与细胞和功能内脏反应的变化相关。对这个项目非常重要，作为一部分 在辅助的Mapp网络中，我们将有一个独特的翻译研究机会。有权访问 包括患者表型和血液样本在内的MAPP资源将进一步加强临床相关性 我们在动物模型中的发现。我们动物模型中的发现将为人类研究提供参考，并可能 引导生物标志物发现。总而言之，我们耐人寻味的初步数据结合我们广泛的专业知识和 资源使我们的研究团队处于独特的地位，可以探索压力诱导的机制 自主神经调节失调可以改变正常的膀胱功能，并可能影响IC/BPS的潜在症状。

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, painful condition associated with urinary frequency and urgency for which there are no proven etiologies and no effective treatments. Evidence supports a role for emotional stress in the exacerbation (and possibly development) of generalized pain syndromes such as IC/BPS as well as micturition disorders. Recent analysis of a patient cohort by the MAPP (multidisciplinary approach for the study of pelvic pain) network has confirmed robust differences between individuals with IC/BPS and healthy controls in psychosocial variables and current and lifetime stress. Although the underlying mechanisms mediating the impact of stress on pain are not well understood, recent evidence shows that chronic stress and bladder dysfunction in IC/BPS may be related to autonomic (adrenergic) dysregulation that influences nociceptive signaling. Our preliminary data have provided evidence for stress-induced autonomic modulation of peripheral targets and mitochondrial functions that are likely to play a role in bladder pain. Taken together, our overall hypothesis is that chronic stress induces autonomic and mitochondrial dysregulation and leads to changes in urothelial-neural signaling influencing voiding and pain behavior. Our research teams will use a multidisciplinary approach including molecular biology, measurement of mitochondrial bioenergetics, electrophysiology and imaging to study the effects of psychological stress in our validated rat chronic water avoidance or WAS model. In Aim #1, we will show that chronic stress increases adrenergic signaling resulting in mitochondrial dysfunction that causes the observed breakdown in the UT barrier. We will measure water and urea permeability and use morphological tools to examine how chronic stress impairs urothelial (UT) regeneration. In Aim #2, we will show increased sympathetic outflow from chronic stress alters UT memory modulated by altered mitochondrial signaling using functional assays (bioenergetics; Ca+2 imaging; measurement of mitochondrial ROS) and molecular approaches. In Aim #3 we will show that chronic stress induces afferent hyperexcitability and spinal cord glial cell activation producing symptom equivalents in IC/BPS. We will examine the distribution and activity of bladder afferents and use genetic tools (designer receptors exclusively activated by designer drugs- DREADDs) to block microglial activation and correlate with changes in cellular and functional visceral responses. Of great importance to this project, as part of the ancillary MAPP network we will have a unique opportunity for translational studies. Having access to MAPP resources including patient phenotypes and blood samples will further strengthen the clinical relevance of our findings in the animal model. Findings in our animal model will inform studies in the human and may guide biomarker discovery. In sum, our intriguing preliminary data combined with our extensive expertise and resources places our research team in a unique position to explore mechanisms by which stress-induced autonomic dysregulation can alter normal bladder function and may influence underlying symptoms in IC/BPS.