Optogenetic dissection of the functional properties of bladder afferent populations

膀胱传入群功能特性的光遗传学解剖

基本信息

批准号：
9324217
负责人：
Jennifer J DeBerry
金额：
$ 13.67万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324217
关键词：
Abdomen Address Afferent Neurons Afferent Pathways Anatomy Behavior Bladder C Fiber Cations Characteristics Chemicals Chronic Chronic Disease Cutaneous Cyclophosphamide Cystitis Cytoskeleton Detection Development Disease Dissection Electromyography Exhibits Fiber Fire - disasters Frequencies Genetic Goals Homeostasis Hyperalgesia Hypersensitivity Increased frequency of micturition Individual Inflammatory Interstitial Cystitis Ion Channel Gating Light MAPK3 gene Mechanics Micturition Reflex Molecular Monitor Nerve Neurons Nociception Nociceptive Reflex Nociceptors Organ Overactive Bladder Pain Pathologic Pathology Pathway interactions Patients Pattern Pelvis Peripheral Persistent pain Phenotype Physiological Population Posterior Horn Cells Preparation Process Property Proteins Reflex action Research Role Sensory Spinal Spinal Cord Stimulus Symptoms TRPV1 gene Techniques Testing Therapeutic Intervention Transgenic Mice Urination Urologic Diseases Visceral Visceral Afferents Visceral pain cell type chemical hypersensitivity cohort defined contribution experience experimental study in vivo light gated micturition urgency mouse model nerve supply neurochemistry neurofilament optogenetics promoter public health relevance receptive field response selective expression targeted treatment treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) and overactive bladder (OAB) are chronic urological disorders characterized by urinary urgency and increased micturition frequency. A defining characteristic of IC that distinguishes it from OAB is the presence of pelvic/suprapubic pain that worsens as the disease progresses. Because visceral innervation is unique (organs are innervated by two nerves) and noxious visceral stimuli are unlike noxious cutaneous stimuli, mechanisms of bladder hypersensitivity differ from those of cutaneous hyperalgesia. Mechanical and/or chemical hypersensitivity of the bladder largely underlies the symptoms experienced by both IC and OAB patients. Yet, because the defining combination of symptoms (urgency and frequency with or without pain) for each cohort differs, and because symptoms arise from a common global population of bladder afferents, selective changes in transduction must occur either within afferent subpopulations, or among the central pathways engaged by afferent subpopulations, or both. These phenomena are poorly understood. Heterogeneous bladder neuronal subpopulations with lightly myelinated or unmyelinated peripheral fibers (A? - and C-fibers, respectively) convey information about multiple processes, including homeostatic monitoring (metaboreceptors) and detection of potentially damaging stimuli (nociceptors). Some fibers exhibit chemosensitivity, and most respond to mechanical stimuli, although some may acquire mechanosensitivity only during pathological conditions. We propose to use transgenic mouse lines expressing the light-gated ion channel, channelrhodopsin-2 (ChR2), in specific subsets of bladder afferents to address their respective contributions to the cardinal symptoms of IC and OAB. We hypothesize that subpopulations of bladder afferents contribute uniquely to micturition processes and nociception. We will test this hypothesis by studying afferent subpopulation contributions: 1) using an ex vivo preparation to functionally evaluate intrinsic and mechanical, chemical, and light-evoked response characteristics, 2) to the expression of in vivo micturition and nociceptive reflexes, and 3) to th activation of neurons receiving bladder afferent input in distinct regions of the spinal cord.

描述（由申请人提供）：间质性膀胱炎（IC）和过度活跃的膀胱（OAB）是慢性泌尿科疾病，其特征是尿液紧急和排尿频率增加。将其与OAB区分开的IC的定义特征是骨盆/映射疼痛的存在随着疾病的发展而恶化。由于内脏神经神经是独特的（器官是两条神经支配的），而有害的内脏刺激与有害的皮肤刺激不同，因此膀胱超敏反应的机制与皮肤痛觉过敏的机制不同。膀胱的机械和/或化学超敏反应在很大程度上是IC和OAB患者所经历的症状。然而，由于每个队列的症状（紧迫性和频率有或没有疼痛的紧迫性和频率）的定义组合不同，并且由于症状是由膀胱传入的普通全球人群引起的，因此转导的选择性变化必须在传入的亚群中发生，或者在被传入的子群中所参与的中心途径中发生。这些现象知之甚少。具有轻微髓鞘或未髓鞘的外周纤维（分别为a？ - 和C纤维）的异质膀胱神经元亚群传达了有关多种过程的信息，包括稳态监测（属于aborececepectors）和检测潜在破坏性损害的刺激（nocieptors）。一些纤维表现出化学敏感性，并且大多数对机械刺激的反应，尽管有些纤维只能在病理条件下获得机械敏感性。我们建议在特定的膀胱传统子集中使用表达光门控通道的转基因小鼠系（CHR2），以解决其对IC和OAB的基本症状的各自贡献。我们假设膀胱传入的亚群对排尿过程和伤害感受唯一贡献。 We will test this hypothesis by studying afferent subpopulation contributions: 1) using an ex vivo preparation to functionally evaluate intrinsic and mechanical, chemical, and light-evoked response characteristics, 2) to the expression of in vivo micturition and nociceptive reflexes, and 3) to th activation of neurons receiving bladder afferent input in distinct regions of the spinal cord.