Mechanisms of neurogenic bladder dysfunction in a viral murine model of multiple sclerosis

多发性硬化症病毒小鼠模型中神经源性膀胱功能障碍的机制

基本信息

批准号：
10047119
负责人：
Anna P Malykhina
金额：
$ 34.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047119
关键词：
Acute Affect Animals Anti-Inflammatory Agents Autonomic ganglion Behavioral Biochemical Biological Assay Bladder Bladder Control Bladder Dysfunction Bladder mucosa Brain Caring Central Nervous System Diseases Chronic Classification Clinical Coronavirus Demyelinations Development Diagnosis Disease Disease remission Electrophysiology (science)Encephalomyelitis Evaluation Functional disorder Gel Gliosis Histology Human Hyaluronic Acid Hydrogels Image Immunohistochemistry Immunotherapeutic agent Immunotherapy Impairment In Vitro Increased frequency of micturition Infection Inflammation Inflammatory Interleukin-10 Laboratories Lesion Link Longterm Follow-up Magnetic Resonance Imaging Mediating Methods Modeling Morphology Motor Multiple Sclerosis Mus Nerve Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurogenic Bladder Neuroglia Neurologic Neurologic Deficit Neuronal Plasticity Neurons Nocturia Overactive Bladder Paper Patients Pattern Peripheral Pharmacogenetics Pharmacology Phase Phenotype Prevention Recovery Relapse Resolution Role Sensory Site Spinal Spinal Cord Stream Structure Subgroup Symptoms Testing Therapeutic United States Update Urge Incontinence Urination Urine Urodynamics Viral Virus Work autoinflammatory base behavioral study cytokine designer receptors exclusively activated by designer drugs experimental study fluorophore glial activation improved in vivo imaging interest lower urinary tract symptoms mouse model multiple sclerosis patient nerve supply neurodegenerative phenotype neuromechanism neurotransmission pressure repaired response translational study

项目摘要

PROJECT SUMMARY Multiple sclerosis (MS) is an auto-inflammatory disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States and more than 2.1 million people worldwide. Lower urinary tract symptoms (LUTS) are present in 70–90% of MS patients, and include urinary frequency, urgency, incontinence, nocturia, incomplete bladder emptying, weak stream, and retention of urine. We recently characterized a new mouse model of neurogenic bladder dysfunction induced by a coronavirus. The virus triggers acute inflammation in the CNS (coronavirus-induced encephalomyelitis, CIE model) followed by progressive demyelination in the brain and spinal cord. CIE mice develop a significant neurologic deficit associated with voiding dysfunction that is comparable with neurogenic LUTS observed in MS patients. The mechanisms underlying neurogenic LUTS in CIE mice include morphological changes in the neuronal centers controlling micturition, activation of spinal glia, increased expression of pro-inflammatory cytokines during acute phase of infection, and enhanced purinergic responses of bladder contractions. Our recent study performed a long-term follow up of CIE mice and revealed 3 differential phenotypes of neurodegenerative symptom development: 1-chronic progression of neurodegeneration with continuous presence of symptoms (C-PRO group), 2 – presence of several remission-relapsing episodes (C-RELAP group), and 3 - recovery from initial symptoms after acute phase of the disease (REC group). Urodynamic evaluation of voiding patterns in each subgroup revealed that mice in C-RELAP group showed the most severe neurogenic bladder overactivity associated with lower bladder capacity, reduced inter-micturition interval, and decreased pressure at micturition. Therefore, the CIE model provides a unique opportunity for the comparison of neurogenic LUTS in three major types of human MS (remissive, chronic and relapsing-remitting). This application builds upon our initial findings, and will uncover the detailed systemic and cellular mechanisms of neurogenic LUTS in order to improve the assessment, diagnosis, and care of LUTS in MS patients. Specific Aim 1 will determine the role of spinal glia activation (gliosis) in modulation of neuronal signaling in the central (spinal) and peripheral (sensory and motor autonomic ganglia) centers involved in the control of micturition. We will evaluate the mechanistic link between glial activation in the spinal cord and functional changes in bladder innervating neurons during early, advanced and chronic stages of MS progression. Specific Aim 2 will test the ability of targeted immunotherapy to improve neurogenic LUTS in a murine model of MS. The proposed experiments will utilize neuroanatomical, biochemical, electrophysiological, pharmacological, pharmacogenetic, immunotherapeutic, and behavioral experiments to provide a comprehensive assessment of the mechanisms underlying the development of neurogenic bladder dysfunction. The results of this study will have a major impact on the diagnosis, treatment and prevention of neurogenic LUTS in patients with neurodegenerative disorders such as MS.

项目概要多发性硬化症 (MS) 是一种影响中枢神经系统 (CNS) 的自身炎症性疾病美国约有 400,000 人，全球有超过 210 万人。 70-90% 的多发性硬化症患者存在尿路症状 (LUTS)，包括尿频、尿急、我们最近出现尿失禁、夜尿、膀胱排空不完全、尿流微弱和尿潴留。该病毒诱导了一种新的神经源性膀胱功能障碍小鼠模型。引发中枢神经系统急性炎症（冠状病毒诱发的脑脊髓炎，CIE 模型），然后 CIE 小鼠的大脑和脊髓进行性脱髓鞘，出现明显的神经功能缺陷。与排尿功能障碍相关，与多发性硬化症患者中观察到的神经源性 LUTS 相当。 CIE 小鼠神经源性 LUTS 的机制包括神经元中枢的形态变化控制排尿、激活脊髓神经胶质细胞、急性期促炎细胞因子的表达增加我们最近的研究进行了一项研究。对 CIE 小鼠的长期随访发现神经退行性症状的 3 种差异表型发展：1-神经变性的慢性进展，并持续出现症状（C-PRO 组），2 – 出现多次缓解-复发发作（C-RELAP 组），3 – 从初始状态恢复疾病急性期后的症状（REC 组）对每个患者的排尿模式进行尿动力学评估。亚组显示，C-RELAP 组的小鼠表现出最严重的神经源性膀胱过度活动与膀胱容量降低、排尿间隔缩短和排尿压力降低有关。因此，CIE 模型为比较三个主要神经源性 LUTS 提供了独特的机会人类多发性硬化症的类型（缓解型、慢性型和复发缓解型）该应用建立在我们的初步发现的基础上，并将揭示神经源性 LUTS 的详细系统和细胞机制，以改善 MS 患者 LUTS 的评估、诊断和护理具体目标 1 将确定脊髓神经胶质细胞的作用。中枢（脊髓）和外周（感觉和运动）神经元信号传导的激活（神经胶质增生）自主神经节）参与排尿控制的中心我们将评估之间的机制联系。早期、晚期脊髓中的神经胶质激活和膀胱神经元的功能变化具体目标 2 将测试靶向免疫疗法改善的能力。 MS 小鼠模型中的神经源性 LUTS 拟议的实验将利用神经解剖学、生物化学、电生理学、药理学、药物遗传学、免疫治疗和行为实验提供对神经源性膀胱发育机制的全面评估这项研究的结果将对功能障碍的诊断、治疗和预防产生重大影响。患有神经退行性疾病（例如 MS）的神经源性 LUTS。