Mechanism of Bladder Overactivity in Pelvic Ischemia

盆腔缺血时膀胱过度活动的机制

• 批准号: 8331737
• 负责人: KAZEM M AZADZOI
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331737
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Age; Aging; Animal Model; Animals; Antioxidants; Anxiety; Atherosclerosis; Benign Prostatic Hypertrophy; Biological Models; Bladder; Blood flow; Bronchioles; Cell Culture Techniques; Chronic; Clinical; Clinical Research; Color Doppler Ultrasonography; Development; Elderly; Elements; Fatigue; Frequencies; Functional disorder; Ganglia; General Population; Goals; Hypoxia; Incidence; Increased frequency of micturition; Indium; Intestines; Ischemia; Lead; Mediating; Mental Depression; Mitochondria; Modeling; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Muscle Contraction; Nerve; Nerve Fibers; Nocturia; Obstruction; Oryctolagus cuniculus; Overactive Bladder; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pelvic Pain; Pelvis; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Population; Predisposing Factor; Prevalence; Production; Quality of life; Reactive Oxygen Species; Regulation; Reporting; Respiration; Respiratory Chain; Role; Severities; Signal Transduction; Sleeplessness; Smooth Muscle; Smooth Muscle Myocytes; Spasm; Stimulus; Stomach; Stress; Symptoms; Synaptosomes; Testing; Therapeutic; Urge Incontinence; Urodynamics; Uterus; Veterans; base; computerized; density; lower urinary tract symptoms; male; novel therapeutics; older patient; prevent; prophylactic; receptor; relating to nervous system; response; transmission process; uptake

DESCRIPTION (provided by applicant): Overactive bladder incorporates to a variety of lower urinary tract symptoms (LUTS) including urinary frequency, urge incontinence, nocturia and pelvic pain. The incidence of bladder overactivity and LUTS increases with age. Clinical studies suggest that the prevalence of bladder overactivity and LUTS among Veterans is almost five fold higher than its incidence in the general population. It has been reported that Veterans with overactive bladder have a worse quality of life score in comparison with Veterans without overactive bladder. In most cases, overactive bladder symptoms are associated with insomnia, anxiety, fatigue, and even depression. Factors predisposing to the development of bladder overactivity and LUTS are poorly understood. In the elderly male, bladder outlet obstruction due to benign prostatic hyperplasia (BPH) has long been blamed. However, urodynamic studies have shown that in approximately one third to more than one-half of cases, LUTS in the elderly are not associated with BPH or bladder outlet obstruction suggesting other possibilities. The specific features of non-obstructed bladder contributing to LUTS remain essentially unknown. We attempt to introduce the concept that aging-associated bladder ischemia is an independent factor in the development of non-obstructed non-neurogenic overactive bladder. Our concept is supported by clinical evidence of a close correlation between bladder ischemia and LUTS in the elderly patients. Blood flow recording with transrectal color Doppler ultrasonography has revealed a significant decrease in bladder blood flow in the elderly patients in comparison with asymptomatic younger controls. It was shown that decreased bladder blood flow significantly correlates with the severity of LUTS in these patients. Ischemia is one of the leading causes of smooth muscle spasm in the stomach, intestine, uterus, and bronchioles. Our studies with a rabbit model have shown that atherosclerosis-induced pelvic ischemia results in bladder overactivity and increased voiding frequency. In preliminary studies, we found that chronic bladder ischemia activated redox survival signaling via phosphoinositide 3-kinase (PI3-Kinase)/protein kinase B (Akt) pathway in smooth muscle cells and nerve fibers. Oxidative stress in cultured smooth muscle cells upregulated redox survival signaling via PI3-kinase and Akt expression and evoked two vital responses to promote survival: 1) Increase in mitochondrial density and respiration rate. 2) Increase in smooth muscle cell Ca++ uptake. These redox survival responses augmented smooth muscle contractions and were associated with bladder overactivity and voiding dysfunction. Inhibition of PI3-Kinase diminished bladder smooth muscle overreactivity to contractile stimuli. Based on these observations, we hypothesize that: "Activation of redox survival signaling via PI3-kinase/Akt pathway in bladder ischemia stimulates smooth muscle and neural mitochondrial respiration and promotes smooth muscle cell Ca++ uptake resulting in excessive contractile activity and voiding dysfunction". Our overall goal is to explore the role of ischemia and redox signaling in bladder overactivity using our well-established animal and cell culture model systems." Our specific aims are: 1) To define redox regulation of bladder smooth muscle contractility via PI3-kinase/Akt survival pathway and mitochondrial respiratory chain under the ischemic conditions. 2) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration and Ca++ uptake by neural redox elements in bladder ischemia. 3) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration, and Ca++ uptake by redox-modified muscarinic receptors in bladder ischemia. 4) To develop therapeutic strategies targeting redox signaling, redox elements and modified receptors to prevent or reverse augmented smooth muscle contractions and bladder overactivity in pelvic ischemia. The proposed studies will elucidate some of the highly controversial aspects of non-obstructed non-neurogenic overactive bladder and may lead to newer therapeutic strategies against bladder overactivity in the elderly population.

描述（由申请人提供）： 过度活跃的膀胱结合到各种下尿路症状（LUTS）中，包括尿频，急性尿失禁，夜尿和骨盆疼痛。膀胱过度活动和LUTS的发生率随着年龄的增长而增加。临床研究表明，在退伍军人中，膀胱过度活动过度和LUT的患病率几乎比普通人群的发病率高五倍。据报道，与没有过度活跃的膀胱的退伍军人相比，膀胱过度活跃的退伍军人的生活质量得分较差。在大多数情况下，过度活跃的膀胱症状与失眠，焦虑，疲劳甚至抑郁有关。散发出膀胱过度活动和LUT的发展的因素知之甚少。在老年男性中，由于前列腺增生（BPH）而引起的膀胱出口阻塞长期以来一直被指责。然而，尿动力学研究表明，在大约三分之一到超过一半的病例中，老年人中的LUT与BPH或膀胱出口阻塞无关，这表明其他可能性。促成LUTS的非刺激性膀胱的特定特征基本未知。我们试图介绍这样的概念，即与衰老相关的膀胱缺血是非刺激性非神经发生过度活跃膀胱发展的独立因素。我们的概念得到了临床证据的支持，表明膀胱缺血与老年患者的LUTS之间存在密切相关。与无症状的年轻对照相比，具有转直肠颜色多普勒超声检查的血流记录显示，老年患者的膀胱血流显着降低。结果表明，膀胱血流降低与这些患者的LUTS严重程度显着相关。缺血是胃，肠，子宫和支气管中平滑肌痉挛的主要原因之一。我们对兔模型的研究表明，动脉粥样硬化诱导的骨盆缺血导致膀胱过度活动过度和空隙频率增加。在初步研究中，我们发现通过磷酸肌醇3-激酶（PI3-激酶）/蛋白激酶B（AKT）在平滑肌细胞和神经纤维中激活的氧化还原生存信号传导。培养的平滑肌细胞中的氧化应激通过PI3-激酶和AKT表达上调了氧化还原存活信号，并引起了两种重要反应以促进生存：1）线粒体密度和呼吸率的增加。 2）增加平滑肌细胞Ca ++摄取。这些氧化还原存活反应增强了平滑肌收缩，并与膀胱过度活动和功能障碍相关。 PI3-激酶的抑制减少了膀胱平滑肌对收缩刺激的过度反应。基于这些观察结果，我们假设：“膀胱缺血中通过PI3-激酶/AKT途径激活氧化还原存活信号传导会刺激平滑肌和神经线粒体呼吸，并促进平滑肌CA ++摄取平滑肌CA ++摄取导致过度的收缩活性和散布的收缩活性和效果失调”。我们的总体目标是 使用我们建立的动物和细胞培养模型系统探索缺血和氧化还原信号传导在膀胱过度活动中的作用。“我们的具体目的是：1）通过PI3-激酶/AKT生存途径和线粒体呼吸链定义膀胱平滑肌收缩性的氧化还原调节，以在等化性群体下进行静置的氛围。途径，线粒体的呼吸和CA ++在膀胱缺血中的神经氧化还原元素的摄取，以定义平滑肌肉细胞PI3-激酶/AKT生存途径的调节，线粒体呼吸，CA ++的ca+ themiation trountries tontrapition troting tontrapity troting bladderiation tontrapity torning 4氧化还原元素和改良的受体可预防或逆转骨盆缺血中的平滑肌收缩和膀胱过度活动。