Mechanism of Bladder Overactivity in Pelvic Ischemia

盆腔缺血时膀胱过度活动的机制

基本信息

批准号：
8965967
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
项目类别：
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/8965967
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 Synaptosomes Testing Therapeutic Urge Incontinence Urodynamics Uterus Veterans associated symptom base computerized density differential expression lower urinary tract symptoms male novel therapeutic intervention older patient prevent prophylactic receptor relating to nervous system response transmission process uptake

项目摘要

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）：膀胱过度活动症会导致多种下尿路症状 (LUTS)，包括尿频、急迫性尿失禁、夜尿和骨盆疼痛。膀胱过度活动症和 LUTS 的发生率随着年龄的增长而增加。临床研究表明，退伍军人中膀胱过度活动症和 LUTS 的患病率几乎是普通人群的五倍。据报道，与没有膀胱过度活动症的退伍军人相比，患有膀胱过度活动症的退伍军人的生活质量得分较差。在大多数情况下，膀胱过度活动症症状与失眠、焦虑、疲劳甚至抑郁有关。人们对膀胱过度活动症和 LUTS 发展的诱发因素知之甚少。在老年男性中，良性前列腺增生（BPH）引起的膀胱出口梗阻长期以来一直受到指责。然而，尿动力学研究表明，在大约三分之一到一半以上的病例中，老年人的 LUTS 与 BPH 或膀胱出口梗阻无关，这表明存在其他可能性。导致 LUTS 的无梗阻膀胱的具体特征仍然基本上未知。我们试图引入这样的概念：与衰老相关的膀胱缺血是非梗阻性非神经源性膀胱过度活动症发展的独立因素。我们的观点得到了老年患者膀胱缺血与 LUTS 之间密切相关的临床证据的支持。经直肠彩色多普勒超声检查的血流记录显示，与无症状的年轻对照相比，老年患者的膀胱血流显着减少。结果表明，膀胱血流量减少与这些患者 LUTS 的严重程度显着相关。缺血是胃、肠、子宫和细支气管平滑肌痉挛的主要原因之一。我们对兔子模型的研究表明，动脉粥样硬化引起的盆腔缺血会导致膀胱过度活动和排尿频率增加。在初步研究中，我们发现慢性膀胱缺血通过平滑肌细胞和神经纤维中的磷酸肌醇 3 激酶 (PI3-激酶)/蛋白激酶 B (Akt) 通路激活氧化还原生存信号。培养的平滑肌细胞中的氧化应激通过 PI3 激酶和 Akt 表达上调氧化还原生存信号，并引发两种促进生存的重要反应：1）线粒体密度和呼吸速率增加。 2) 增加平滑肌细胞Ca++摄取。这些氧化还原生存反应增强了平滑肌收缩，并与膀胱过度活动和排尿功能障碍有关。抑制 PI3 激酶可减少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：“膀胱缺血时通过 PI3 激酶/Akt 通路激活氧化还原生存信号，刺激平滑肌和神经线粒体呼吸，促进平滑肌细胞 Ca++ 摄取，导致过度收缩活动和排尿功能障碍”。我们的总体目标是使用我们完善的动物和细胞培养模型系统探索缺血和氧化还原信号在膀胱过度活动中的作用。”我们的具体目标是：1) 通过 PI3 激酶/Akt 生存途径和线粒体来定义膀胱平滑肌收缩性的氧化还原调节2) 确定膀胱缺血时神经氧化还原元件对平滑肌细胞 PI3 激酶/Akt 存活途径、线粒体呼吸和 Ca++ 摄取的调节。 3) 明确膀胱缺血中氧化还原修饰毒蕈碱受体对平滑肌细胞 PI3 激酶/Akt 存活途径、线粒体呼吸和 Ca++ 摄取的调节 4) 开发针对氧化还原信号、氧化还原元件和修饰受体的治疗策略以预防。或逆转盆腔缺血时增强的平滑肌收缩和膀胱过度活动。拟议的研究将阐明非阻塞性非神经源性的一些备受争议的方面。膀胱过度活动症可能会导致针对老年人膀胱过度活动症的新治疗策略。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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一种在体外攻击同种异体癌细胞的新型 IgM-H-ficolin 补体途径。

DOI：
发表时间：
2015-01-16
期刊：
影响因子：
4.6
作者：
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DOI：
发表时间：
2017
期刊：
影响因子：
3.3
作者：
Bi, Baibin;Li, Feng;Guo, Jisheng;Li, Cuiling;Jing, Ruirui;Lv, Xin;Chen, Xinjun;Wang, Fengqin;Azadzoi, Kazem M;Wang, Lin;Liu, Yuguang;Yang, Jing
通讯作者：
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