Role of Mechanotransduction in detrusor over activity

机械转导在逼尿肌过度活动中的作用

• 批准号: 9104155
• 负责人: Anna P Malykhina
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104155
• 关键词: Actins; Address; Affect; Afferent Neurons; Bladder; Bladder Dysfunction; Caveolins; Cell Line; Cytoskeleton; Data; Development; Disease; Electrophysiology (science); Exhibits; Family; Foundations; Functional disorder; Gene Activation; Gene Expression; Gene Silencing; Health; Human; Interstitial Cystitis; Intervention; Lead; Lower urinary tract; Mechanics; Medical; Membrane Lipids; Microfilaments; Molecular; Muscle Cells; Organ; Overactive Bladder; Patients; Physiological; Play; Potassium Channel; Proteins; Psychological Stress; Quality of life; Regulation; Relaxation; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Spinal Cord; Stimulus; Stretching; Symptoms; Techniques; Temperature; Testing; Therapeutic Effect; Up-Regulation; Urinary Incontinence; Urination; Vascular Smooth Muscle; Visceral; animal data; biophysical properties; caveolin 1; diabetic; efficacy testing; gene therapy; genetic approach; innovation; member; membrane activity; mutation screening; novel; polymerization; potassium channel protein TREK-1; pressure; promoter; receptor; research study; response; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Mechanosensitivity of the detrusor is defined as the ability of smooth muscle cells to generate mechanical activity independent of external stimuli. During bladder filling, there is usually no parasympathetic outflow from the spinal cord, however, the bladder develops tone and also exhibits non- synchronized local contractions and relaxations. Pathological changes in mechanosensory mechanisms may lead to the development of detrusor overactivity (DO) which is a co-symptom of several dysfunctions of the lower urinary tract including overactive bladder, obstructed bladder, urinary incontinence, and bladder pain syndrome. The central hypothesis of this proposal is that impaired mechanosensation and mechanotransduction in bladder smooth muscle cells (BSMC) results in the abnormal response of the human bladder to physiological stretch and detrusor overactivity due to the changes in mechano-gated two-pore domain (K2p, KCNK) K+ channels. Animal data and our preliminary results from the human detrusor suggest that stretch-activated two-pore domain (K2p, KCNK) K+ channels play a critical role in bladder mechanosensitivity. We also established that TREK-1 channel is a predominantly expressed member of stretch-activated K2p channels in the human detrusor. Specific Aim 1 will identify differences in the level of expression and function of stretch-activated K+ (K2p) channels in human bladder smooth muscle cells in patients without and with detrusor overactivity. Specific Aim 2 will evaluate interactions between TREK-1 and cytoskeleton (actin microfilaments, caveolin, membrane lipids) in human BSMC and compare the role of TREK-1 modulating proteins in normal vs. overactive human detrusor. Specific Aim 3 will test the efficacy of gene therapies (gene silencing by siRNA and gene activation by saRNA) in modulating the expression and function of TREK-1 in human BSMC in order to effectively regulate an abnormal response of the overactive detrusor to stretch during bladder filling. The overall objective of this proposal is to investigat cellular and molecular mechanisms of abberant mechanosensitivity and altered response of the human detrusor to physiological stretch associated with increased myogenic tone and spontaneous non-voiding contractions in patients with DO. Proposed studies will clarify the cellular mechanisms of mechanosensitivity and mechanotransduction in the human bladder and in patients with idiopathic DO, and provide new information for the development of new pharmacological interventions and innovative strategies for the treatment of urinary bladder dysfunctions.

描述（由申请人提供）：批准器的机械敏感性定义为平滑肌细胞产生与外部刺激无关的机械活动的能力。在膀胱填充过程中，通常没有脊髓的副交感流出，但是，膀胱会发育张力，并且表现出非同步的局部收缩和放松。机械强度机制的病理变化可能导致迫切过度活跃（DO）的发展，这是下尿路的几种功能障碍的共同症状，包括过度活跃的膀胱，膀胱阻塞，尿失禁，尿失禁和膀胱疼痛综合征。该提议的中心假设是，膀胱平滑肌细胞（BSMC）的机械敏化和机械转移受损导致人膀胱对生理伸展的异常反应，并且由于机械门控的两孔域（K2P，KCNK，KCNK）K+通道的变化而导致人体膀胱对生理伸展和偏心过度活动。动物数据和我们的初步结果来自人类的逼尿肌，这表明拉伸激活的两孔域（K2P，KCNK）K+通道在膀胱机械敏感性中起着至关重要的作用。我们还确定，Trek-1通道主要是人类逼rusor中拉伸激活的K2P通道的成员。具体的目标1将确定人膀胱平滑肌细胞中没有迫害者过度活动过度的患者中人膀胱平滑肌细胞中拉伸激活的K+（K2P）通道的表达和功能水平的差异。特定的目标2将评估Trek-1和细胞骨架（肌动蛋白微丝，小窝蛋白，膜脂质）之间的相互作用，并比较Trek-1调节蛋白在正常和过度活跃的人类损坏中的作用。具体的目标3将测试基因疗法（siRNA的基因沉默和SARNA基因激活的基因沉默）在调节人BSMC中Trek-1的表达和功能，以有效调节过度活跃逆转的异常反应，以在膀胱填充过程中伸展。该提议的总体目的是研究透明机械敏感性的细胞和分子机制，并改变了人类对生理延伸的反应改变，与肌原性张力和自发性非散热收缩有关的生理伸展。拟议的研究将阐明人膀胱和特发性DO患者的机械敏感性和机械转导的细胞机制，并为开发新的药理干预措施和创新策略提供新的信息，以治疗膀胱功能障碍。