REGULATION OF DETRUSOR SMOOTH MUSCLE CONTRACTION

描述（由申请人提供）：膀胱过度活动症是一种使人衰弱的 以增加的尿频、尿急或尿失禁为特征的疾病。 在美国，膀胱过度活动症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，膀胱过度活动症的病因 仍然未知。目前药物治疗过度活跃的目的 膀胱没有达到选择性减少非自愿性的目标， 逼尿肌平滑肌（DSM）的活动，而不影响其他器官， 减少膀胱充盈期间而不是排尿期间的逼尿肌收缩。 用于治疗过度活跃的新型药物的发现 膀胱等待识别特定于DSM的调节机制 收缩。我的实验室的长期目标是精确识别 调节DSM收缩蛋白激活的亚细胞机制， 鉴定治疗泌尿疾病如活动过度 膀胱 当刺激升高[Ca2 +] i时，平滑肌收缩发生。但最近的 研究表明，收缩蛋白对Ca2+的敏感性增加， 这是一个同样重要的监管机制。最近发现， 血管平滑肌Ca 2+敏感性的过度活动参与了 高血压的病理生理学为研究和 了解所有平滑肌类型中Ca2+敏化的生理学。 这一发现也提出了过度激活的Ca 2+敏化 会导致膀胱过度活动症目标1将检验以下假设： Ca~（2+）敏感性在OSM收缩的调节中起重要作用。 无论RhoA激酶、磷脂酶A2产生的花生四烯酸或 细胞外信号调节激酶激活的钙调蛋白 磷酸化，参与Ca2+敏感诱导的收缩， 测试，和具体的作用M2受体在这一途径将发挥 测定目的2将检验逼尿肌伸展和β-肾上腺素能增加的假设。 肾上腺素能受体刺激通过激活cAMP依赖性蛋白来放松DSM 激酶，其降低[Ca2 +] i和Ca2+敏感性。telokin的程度 磷酸化、RhoA失活和ERK诱导的钙调蛋白的减少 磷酸化参与降低的Ca2+敏感性将被阐明。 总的来说，这些研究将为细胞生物学提供新的见解。 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.