REGULATION OF DETRUSOR SMOOTH MUSCLE CONTRACTION

描述(申请人提供)：过度活跃的膀胱是一种衰弱 以尿频、尿急或大小便失禁为特征的疾病。 在美国，膀胱过度活跃是一种比糖尿病更常见的慢性疾病 或消化性溃疡，然而，对于大多数情况下，膀胱过度活跃的病因 仍然不为人知。活动性亢进的现代药物治疗目标 膀胱没有达到选择性减少非自愿的目标 在不影响其他器官的情况下，逼尿肌平滑肌(DSM)的活动，并 减少膀胱充盈时的逼尿肌收缩，而不是排尿时。 治疗多动症的新型药理药物的发现 膀胱等待DSM特有的调节机制的确定 收缩。我的实验室的长期目标是准确地识别 调节DSM收缩蛋白激活的亚细胞机制，并 确定治疗尿路疾病的治疗药物，如过度活跃 膀胱。 当刺激升高[Ca~(2+)]i时，就会发生平滑肌收缩。然而，最近 研究表明，收缩蛋白对钙离子的敏感性增加 代表着一种同样重要的监管机制。最近的发现是 血管平滑肌钙敏化的过度活动参与了 高血压的病理生理学为研究和治疗高血压提供了动力 了解所有类型的平滑肌中钙离子敏化的生理学。 这一发现也提出了一种可能性，即过度活跃的钙敏化 会导致膀胱过度活跃。目标1将检验假设 Ca~(2+)敏感性在OSM收缩的调节中起重要作用。 无论是RhoA激酶、磷脂酶A2生成的花生四烯酸还是 细胞外信号调节蛋白激酶(ERK)激活的钙调蛋白 磷酸化，参与钙离子敏化诱导的收缩 测试，M2受体在这一途径中发挥的具体作用将是 下定决心。目标2将检验逼尿肌伸展和贝塔的假说 肾上腺素能受体刺激通过激活cAMP依赖蛋白来松弛DSM 它能降低[Ca~(2+)]i和钙敏感性。远程登录的程度 ERK诱导的钙调蛋白的磷酸化、RhoA失活和减少 磷酸化参与了钙敏感性降低的过程将会被阐明。 总而言之，这些研究将提供对细胞 调节DSM收缩的机制。

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.