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

基本信息

批准号：
10425403
负责人：
LORI A BIRDER
金额：
$ 68.43万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425403
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

项目摘要

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) 是一种与泌尿相关的慢性疼痛性疾病其频率和紧迫性尚未得到证实，也没有有效的治疗方法。证据支持情绪压力在全身性疼痛综合征的恶化（以及可能的发展）中发挥作用，例如如 IC/BPS 以及排尿障碍。 MAPP（多学科）最近对患者队列进行的分析研究盆腔疼痛的方法）网络已证实患有以下疾病的个体之间存在显着差异 IC/BPS 和心理社会变量以及当前和一生压力的健康控制。虽然底层调节压力对疼痛影响的机制尚不清楚，最近的证据表明 IC/BPS 中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。我们的初步数据为压力诱发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疼痛中发挥作用。采取总之，我们的总体假设是，慢性压力会诱发自主神经和线粒体失调并导致尿路上皮神经信号变化，影响排尿和疼痛行为。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、电生理学和成像技术来研究心理压力对我们的影响验证了大鼠慢性回避水或 WAS 模型。在目标#1中，我们将证明慢性压力会增加肾上腺素信号传导导致线粒体功能障碍，导致 UT 中观察到的故障障碍。我们将测量水和尿素的渗透性，并使用形态学工具来检查慢性压力会损害尿路上皮 (UT) 再生。在目标#2中，我们将显示慢性病引起的交感神经流出增加。压力会改变UT记忆，而UT记忆是通过功能测定（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，我们将证明慢性应激诱导传入过度兴奋和脊髓神经胶质细胞活化产生症状 IC/BPS 中的等效项。我们将检查膀胱传入神经的分布和活动并使用遗传工具（仅由设计药物 DREADD 激活的设计受体）阻止小胶质细胞激活与细胞和功能性内脏反应的变化相关。作为该项目的一部分，该项目非常重要通过辅助 MAPP 网络，我们将获得独特的转化研究机会。有权访问包括患者表型和血液样本在内的 MAPP 资源将进一步增强临床相关性我们在动物模型中的发现。我们的动物模型中的发现将为人类研究提供信息，并可能指导生物标志物发现。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，可以探索压力诱发的机制自主神经失调会改变正常的膀胱功能，并可能影响 IC/BPS 的潜在症状。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stress-Induced Changes in Trophic Factor Expression in the Rodent Urinary Bladder: Possible Links With Angiogenesis.

DOI：
10.5213/inj.2244118.059
发表时间：
2022-12
期刊：
International neurourology journal
影响因子：
2.3
作者：
de Rijk MM;Wolf-Johnston A;Kullmann AF;Maringer K;Sims-Lucas S;van Koeveringe GA;Rodríguez LV;Birder LA
通讯作者：
Birder LA

Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019.

DOI：
10.1002/nau.24313
发表时间：
2020-07
期刊：
NEUROUROLOGY AND URODYNAMICS
影响因子：
2
作者：
Speich, John E.;Tarcan, Tufan;Hashitani, Hikaru;Vahabi, Bahareh;McCloskey, Karen D.;Andersson, Karl-Erik;Wein, Alan J.;Birder, Lori A.
通讯作者：
Birder, Lori A.

Aging-Associated Changes in Oxidative Stress Negatively Impacts the Urinary Bladder Urothelium.

DOI：
10.5213/inj.2142224.112
发表时间：
2022-06
期刊：
INTERNATIONAL NEUROUROLOGY JOURNAL
影响因子：
2.3
作者：
de Rijk, Mathijs M.;Wolf-Johnston, Amanda;Kullmann, Aura F.;Taiclet, Stephanie;Kanai, Anthony J.;Shiva, Sruti;Birder, Lori A.
通讯作者：
Birder, Lori A.

Stress-induced autonomic dysregulation of mitochondrial function in the rat urothelium.

DOI：
10.1002/nau.23876
发表时间：
2019-03
期刊：
Neurourology and urodynamics
影响因子：
2
作者：
Kullmann FA;McDonnell BM;Wolf-Johnston AS;Kanai AJ;Shiva S;Chelimsky T;Rodriguez L;Birder LA
通讯作者：
Birder LA

Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome.