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

压力引起的自主神经和尿路上皮失调对 IC/BPS 的影响

• 批准号: 9767129
• 负责人: LORI A BIRDER
• 金额: $ 71.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767129
• 关键词: Adrenal Glands; Adrenergic Agents; Adrenergic Receptor; Affect; Anatomy; Animal Model; Animals; Back; Bioenergetics; Biological Assay; Bladder; Bladder Diseases; Bladder Dysfunction; Blood specimen; Calcium; Catecholamines; Chronic; Chronic stress; Clinical; Complex; Confocal Microscopy; Data; Development; Disease; Distributional Activity; Electrophysiology (science); Emotional Stress; Etiology; Event; Family Felidae; Flare; Foundations; Functional disorder; Future; Genetic; Human; Hypothalamic structure; Image; Impaired wound healing; Impairment; Increased frequency of micturition; Individual; Interstitial Cystitis; Lead; Letters; Link; Literature; Lower urinary tract; Maintenance; Measurement; Measures; Mediating; Medical; Memory; Microglia; Mitochondria; Modeling; Molecular; Molecular Biology; Morphology; Natural regeneration; Nerve; Nervous System Physiology; Nervous system structure; Neuroglia; Neurologic; Neurons; Nociception; Organ; Oxidative Stress; Pain; Pain Disorder; Pathologic; Patients; Pelvic Pain; Peripheral; Permeability; Phenotype; Physicians; Pituitary Gland; Play; Positioning Attribute; Process; Proliferating; Psychological Stress; Psychosocial Factor; Quantitative Reverse Transcriptase PCR; Rattus; Reactive Oxygen Species; Regenerative response; Regulation; Reporting; Research; Resistance; Resources; Rodent; Role; Sampling; Sensory; Signal Pathway; Signal Transduction; Spinal; Spinal Cord; Stress; Sum; Symptoms; Syndrome; System; Translating; Urea; Urination; Urologic Diseases; Urothelial Cell; Urothelium; Visceral; Water; Western Blotting; Work; afferent nerve; biomarker discovery; bladder pain; chronic painful condition; clinically relevant; cohort; designer receptors exclusively activated by designer drugs; effective therapy; experimental study; glial activation; interdisciplinary approach; micturition urgency; mitochondrial dysfunction; neurotransmission; novel strategies; pain behavior; repaired; response; sensory input; tool; translational study

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.

间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种与泌尿系统疾病相关的慢性疼痛性疾病。 频率和紧迫性，没有经过证实的病因和有效的治疗方法。证据支持 情绪压力在全身性疼痛综合征的恶化（可能发展）中的作用， 如IC/BPS以及排尿障碍。MAPP（多学科）对患者队列的最新分析 研究盆腔疼痛的方法）网络已经证实了个体之间的强大差异， IC/BPS和健康对照的心理社会变量和当前和终身压力。虽然根本 调节压力对疼痛影响的机制还不清楚，最近的证据表明， IC/BPS患者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， 影响伤害性信号传导。我们的初步数据为应激诱导的自主神经功能提供了证据。 调节外周靶点和线粒体功能，可能在膀胱疼痛中发挥作用。采取 总之，我们的总体假设是，慢性应激诱导自主神经和线粒体 调节失调，并导致影响排尿和疼痛的尿道神经信号的变化 行为我们的研究团队将采用多学科方法，包括分子生物学，测量 线粒体生物能量学，电生理学和成像，以研究心理应激对我们的影响。 经验证的大鼠慢性避水或WAS模型。在目标1中，我们将展示慢性压力会增加 肾上腺素能信号传导导致线粒体功能障碍，导致UT中观察到的崩溃 屏障我们将测量水和尿素的渗透性，并使用形态学工具来研究慢性 应激损害尿路上皮（UT）再生。在目标#2中，我们将显示慢性交感神经流出增加， 使用功能测定（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 慢性应激诱发传入兴奋过度和脊髓胶质细胞激活产生症状 IC/BPS中的等效值。我们将检查膀胱传入神经的分布和活动，并使用遗传工具 （设计者受体专门由设计者药物激活-DREADD）来阻断小胶质细胞激活， 与细胞和功能性内脏反应的变化相关。对这个项目来说非常重要， MAPP的辅助网络，我们将有一个独特的机会，转化研究。能够访问 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。我们在动物模型中的发现将为人类研究提供信息， 指导生物标志物的发现。总之，我们有趣的初步数据结合了我们广泛的专业知识， 资源使我们的研究团队处于一个独特的位置，以探索压力诱导的机制。 自主神经失调可改变正常膀胱功能，并可能影响IC/BPS的潜在症状。