Remodeling of Smooth Muscle in Bladder Outlet Obstructi*

宾夕法尼亚大学乔治·M·奥布莱恩泌尿学研究中心是一个跨机构、多学科的项目，其重点是研究部分性膀胱出口梗阻(PBOO)中平滑肌功能障碍的分子机制。该中心有三个关键要素：1)由五名主要研究人员和合作人员组成的实验室，他们带来了分子生物学、细胞生物学、生物化学、生理学、药理学和病理学方面的专业知识；2)行政核心(核心A)，以提供行政管理 项目的监督、项目的质量控制、泌尿中心研究和互动的协调；以及3)膀胱组织核心(核心B)，作为PBOO动物模型(兔和小鼠)的平滑肌肉组织以及手术标本中的人类膀胱组织的来源。这些项目是：1：梗阻反应中细胞外基质的变化(Macarak)，2：细胞外基质和拉伸对逼尿肌重建过程中平滑肌表型表达的影响(DiSanto)，3：细胞和分子 逼尿肌收缩和膀胱功能障碍在梗阻诱导的逼尿肌重塑中的基础(CHACKO)，以及4A和B：出口梗阻后膀胱重塑中跨桥循环的调节机制和力的产生和维持(Moland&Barsotti)。此外，我们有两个核心，一个膀胱组织核心(Zderic)和一个行政核心(Chacko&Wein)，以及两个试点和可行性项目。它们是：1)用环孢素Zderic抑制钙化尿路导致出口梗阻的逼尿肌肥大；(2)膀胱梗阻时磷脂酶的激活(LaBelle)。新提案 将决定哪些信号转导通路导致钙敏感性、肌动蛋白-肌球蛋白相互作用、跨桥循环，以及它们在重塑的逼尿肌中如何改变。此外，这将有助于确定在去除梗阻后哪些变化是可逆的，以及在即使梗阻逆转后仍功能障碍的膀胱中哪些分子事件是不可逆的。这些研究的数据将有助于阐明PBOO后逼尿肌收缩能力改变的细胞/分子基础，识别可用于确定哪些梗阻性膀胱被重塑到收缩功能障碍不可逆转的程度的分子标志物，并针对分子步骤开发治疗方法。

The George M. O'Brien Urology Research Center at the University of Pennsylvania is an inter-institutional, multidisciplinary program that focuses its research on the molecular mechanisms underlying smooth muscle dysfunction in partial urinary bladder outlet obstruction (PBOO). The Center has three key elements: 1) the laboratories of five principal investigators and Co-PIs who bring expertise in molecular biology, cellular biology, biochemistry, physiology, pharmacology, and pathology; 2) an administrative core (Core A) to provide administrative oversight, quality control of projects, coordination of the research and interactions in the Urology Center; and 3) a bladder tissue core (Core B) to serve as a resource for smooth muscle tissue from animal models (rabbits and mice) for PBOO as well as human bladder tissue from surgical specimens. The projects are, 1: Extracellular Matrix Changes in Response to Obstruction (Macarak), 2: Effect of Extracellular Matrix and Stretch on the Expression of Smooth Muscle Phenotype during Detrusor Smooth Muscle Remodeling (DiSanto), 3: Cellular and Molecular Basis of Detrusor Contractility and Bladder Dysfunction in obstruction-induced detrusor remodeling (Chacko), and 4 A&B: Mechanism for the regulation of cross-bridge cycling and force generation and maintenance in bladder remodeling following outlet obstruction (Moreland & Barsotti). In addition, we have two Cores, a Bladder Tissue Core (Zderic), and an Administrative Core (Chacko & Wein), and two Pilot & Feasibility Projects. These are 1) Dimunition of Detrusor Hypertrophy in Outlet Obstruction by Inhibition of Calcineurine Pathway with Cyclosporin (Zderic) and (2) Phospholipase Activation During Bladder Obstruction (LaBelle). The new proposal will determine which signal transduction pathways lead to Ca2+-sensitization, actin-myosin interaction, crossbridge cycling, and how they are altered in the remodeling detrusors. Furthermore, it will help to establish which changes are reversible upon removal of the obstruction, and which molecular events are not reversible in the bladders that continue to be dysfunctional even after reversal of the obstruction. Data from these studies would help elucidate the cellular/molecular basis for the alteration of detrusor contractility following PBOO, to identify molecular markers that can be used to determine which obstructed bladder is remodeled beyond a point that contractile dysfunction is irreversible, and to target molecular steps for developing therapy.