Mouse Urinary Bladder Identifying Targets to Treat Overactive Bladder

小鼠膀胱识别治疗膀胱过度活动症的靶标

• 批准号: 8630548
• 负责人: EUGENE M SILINSKY
• 金额: $ 15.08万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630548
• 关键词: Acetylcholine; Address; Adenosine; Adenosine A1 Receptor; Age; Animals; Automobile Driving; Behavior; Bladder; Bladder Dysfunction; Bladder Tissue; Botulinum Toxins; Caregivers; Cleaved cell; Clinical; Clinical effectiveness; Collaborations; Development; Disease; Distress; Employee Strikes; Epithelial; Exhibits; FDA approved; Figs - dietary; Functional disorder; Human; In Vitro; Inflammation; Measures; Mediating; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Muscarinics; Muscle Contraction; Nerve; Neuromodulator; Neurons; Overactive Bladder; P2X-receptor; Parkinson Disease; Pathway interactions; Patients; Physiological; Play; Preparation; Purinergic P1 Receptors; Relative (related person); Research Personnel; Role; Sampling; Secretory Component; Site; Specimen; Study models; Symptoms; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Toxin; Urinary Incontinence; Urothelium; analog; channel blockers; cholinergic; detrusor muscle; effective therapy; human tissue; in vivo; inhibitor/antagonist; innovation; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; public health relevance; receptor; research study; therapeutic target; transmission process; uptake; vesamicol

DESCRIPTION (provided by applicant): Overactive bladder (OAB) is a major cause of distress for patients and their caregivers. The long term objective of this proposal is to identify novel therapeutic intervention sites for treating OAB. As the purinergic component of contraction of the bladder detrusor muscle (mediated by ATP) is increased in OAB relative to the normal cholinergic component, we propose that prejunctional mechanisms governing ATP release will provide impactful targets for controlling detrusor activity and voiding behavior. We will use electrophysiological and muscle contraction techniques in mouse and human tissues to address 3 Specific Aims. SPECIFIC AIM 1: Determine the pre-junctional physiological mechanisms controlling the detrusor muscle of the bladder by: A. measuring the contributions of neuronal Ca2+ channel subtypes in controlling ATP versus acetylcholine (ACh) release;. B. Defining the therapeutic effects of the bolultinum toxin (Botx) fractions (A-E) as they cleave specific components of the nerve terminal secretory apparatus, and C. Determine the effects of (-)-vesamicol (ACh uptake inhibitor) on the purinergic and cholinergic components. SPECIFIC AIM 2: Determine the actions of adenosine receptors on detrusor neurotransmission. Our preliminary experiments show that A1 adenosine receptor analogs modulate detrusor activity. To exploit this we will define the role of these receptors as neuromodulators and measure the influence of epithelial components (urothelium/suburothelium) on neurotransmission and release. This is critical as we recently found that urothelial adenosine derivatives inhibit detrusor contractions suggesting a mechanism for modulating activity and symptoms. Such translational findings will be tested in human detrusor confirming the site and mechanism of adenosine-mediated inhibition. SPECIFIC AIM 3: To study murine models of OAB and bladder dysfunction utilizing a newly developed in vivo voiding mouse that mimics human OAB, we will: A. Determine purinergic/cholinergic transmission ratios and B. Test the effects of Ca2+ channel blockers, adenosine analogs, and BoTx fractions. These studies will integrate the murine and human findings in a setting that confirms clinical targets and therapeutic pathways.

描述（由申请人提供）：膀胱过度活动症（OAB）是患者及其护理人员痛苦的主要原因。本提案的长期目标是确定 用于治疗OAB的新的治疗干预部位。由于膀胱逼尿肌收缩的嘌呤能成分（由ATP介导）相对于正常胆碱能成分在OAB中增加，我们提出，支配ATP释放的连接前机制将为控制逼尿肌活动和排尿行为提供有效的靶点。我们将在小鼠和人体组织中使用电生理和肌肉收缩技术，以解决3个特定目标。具体目的1：确定控制膀胱逼尿肌的连接前生理机制：A。测量神经元Ca 2+通道亚型在控制ATP相对于乙酰胆碱（ACh）释放中的贡献; B。确定Bolultinum毒素（Botx）组分（A-E）的治疗作用，因为它们切割神经末梢分泌器的特定组分，以及C.测定乙酰胆碱摄取抑制剂（-）-维索霉素对嘌呤能和胆碱能成分的影响。具体目的2：确定腺苷受体对逼尿肌神经传递的作用。我们的初步实验表明，A1腺苷受体类似物调节逼尿肌活动。为了利用这一点，我们将定义这些受体作为神经调质的作用，并测量上皮成分（urothelatin/sububurothelatin）对神经传递和释放的影响。这是至关重要的，因为我们最近发现，尿路上皮腺苷衍生物抑制逼尿肌收缩，提示调节活动和症状的机制。将在人逼尿肌中测试这种翻译结果，以确认腺苷介导的抑制的位点和机制。具体目标3：为了利用新开发的模拟人OAB的体内排尿小鼠研究OAB和膀胱功能障碍的小鼠模型，我们将：测定嘌呤能/胆碱能传递比和B。测试Ca 2+通道阻滞剂、腺苷类似物和BoTx组分的作用。这些研究将在确认临床靶点和治疗途径的环境中整合鼠和人的发现。

项目成果

A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder.

A1 腺苷受体介导的人和小鼠膀胱副交感神经肌肉传递的抑制。

• DOI: 10.1124/jpet.115.228882
• 发表时间: 2016
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Searl,TimothyJ;Dynda,DanutaI;Alanee,ShaheenR;El-Zawahry,AhmedM;McVary,KevinT;Silinsky,EugeneM
• 通讯作者: Silinsky,EugeneM