REGULATION OF DETRUSOR SMOOTH MUSCLE CONTRACTION

逼尿肌平滑肌收缩的调节

• 批准号: 6437310
• 负责人: PAUL H RATZ
• 金额: $ 24.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6437310
• 关键词: arachidonate; beta adrenergic receptor; biological signal transduction; biomechanics; calcium indicator; electromyography; electrophysiology; enzyme inhibitors; gene expression; human tissue; intermolecular interaction; laboratory rabbit; molecular pathology; muscarinic receptor; muscle contraction; muscle pharmacology; phosphorylation; posttranslational modifications; protein kinase; protein structure function; smooth muscle; urinary bladder disorder; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Overactive bladder is a debilitating disorder characterized by increased urinary frequency, urgency or incontinence. In the US, overactive bladder is a more common chronic condition than diabetes or peptic ulcer, yet, for most cases, the etiology of overactive bladder remains unknown. The aim of current pharmacologic treatment of overactive bladder has fallen short of its target to selectively reduce involuntary activity of detrusor smooth muscle (DSM) without affecting other organs, and to reduce detrusor contractions during bladder filling, and not during voiding. The discovery of novel pharmacological agents for the treatment of overactive bladder awaits the identification of regulatory mechanisms specific to DSM contraction. The long-term goal of my laboratory is to precisely identify the subcellular mechanisms that regulate DSM contractile protein activation, and to identify therapeutic agents to treat urinary conditions such as overactive bladder. Smooth muscle contractions occur when stimuli elevate [Ca2+]i. However, recent studies demonstrate that increased sensitivity of contractile proteins to Ca2+ represents an equally important regulatory mechanism. The recent discovery that overactivity of vascular smooth muscle Ca2+-sensitization is involved in the pathophysiology of hypertension has provided the impetus to study and understand the physiology of Ca2+-sensitization in all smooth muscle types. This discovery also raises the possibility that overactive Ca2+-sensitization contributes to overactive bladder. Aim 1 will test the hypothesis that Ca2+-sensitivity plays an essential role in regulation of OSM contractions. Whether RhoA kinase, phospholipase A2-generated arachidonic acid or extracellular signal-regulated kinase (ERK)-activated caldesmon phosphorylation, participate in Ca2+-sensitization-induced contractions will be tested, and the specific role M2 receptors play in this pathway will be determined. Aim 2 will test the hypothesis that detrusor-stretch and beta adrenergic receptor stimulation relax DSM by activating cAMP-dependent protein kinase, which reduces [Ca2+]i and Ca2+-sensitivity. The degree to which telokin phosphorylation, inactivation of RhoA, and reductions in ERK-induced caldesmon phosphorylation participate in reduced Ca2+-sensitivity will be elucidated. Collectively, these studies will provide new insights into the cellular mechanisms regulating DSM contractions.

描述（由申请人提供）：过度活跃的膀胱是令人衰弱的 疾病的特征是增加尿频，紧迫性或尿失禁。 在美国，过度活跃的膀胱比糖尿病更常见 或消化性溃疡，但在大多数情况下，过度活跃的病因 仍然未知。当前过度活跃的药理治疗的目的 膀胱未达到其目标，以选择性地减少非自愿性 迫害者平滑肌（DSM）的活性，而不会影响其他器官，并且 减少膀胱填充期间的逼尿肌收缩，而不是在排空期间。 发现新型药理学剂用于治疗过度活跃 膀胱等待鉴定DSM特有的调节机制 收缩。我实验室的长期目标是精确确定 调节DSM收缩蛋白激活的亚细胞机制，并 识别治疗剂以治疗尿液状况（例如过度活跃） 膀胱。 当刺激升高[Ca2+] i时，会出现平滑肌收缩。但是，最近 研究表明，收缩蛋白对Ca2+的敏感性提高 代表同样重要的调节机制。最近发现 血管平滑肌Ca2+ - 敏化的过度活动与 高血压的病理生理学提供了研究的动力和 了解所有平滑肌类型中Ca2+ - 敏化的生理学。 这一发现还增加了过度活跃的Ca2+敏化的可能性 导致膀胱过度活跃。 AIM 1将检验以下假设 CA2+ - 敏感性在OSM收缩调节中起着至关重要的作用。 是RhoA激酶，磷脂酶A2生成的花生四烯酸还是 细胞外信号调节激酶（ERK）激活的Caldesmon 磷酸化，参与Ca2+ - 敏化引起的收缩将是 测试，M2受体在此途径中扮演的特定角色将是 决定。 AIM 2将检验以下假设的假设 肾上腺素能受体刺激通过激活cAMP依赖性蛋白质松弛DSM 激酶，降低[Ca2+] I和Ca2+ - 敏感性。 Telokin的程度 RhoA的磷酸化，灭活以及ERK诱导的Caldesmon的减少 将阐明磷酸化参与Ca2+敏感性降低。 总的来说，这些研究将为细胞提供新的见解 调节DSM收缩的机制。