Remodeling of Smooth Muscle in Bladder Outlet Obstructi*

该乔治M。宾夕法尼亚大学奥布莱恩泌尿学研究中心是一个跨机构的多学科项目，其研究重点是部分膀胱出口梗阻（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）五名主要研究者和合作PI的实验室，他们带来分子生物学，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）一个管理核心（核心A），提供行政管理。 监督、项目的质量控制、研究的协调和泌尿中心的相互作用;和3）膀胱组织核心（核心B），用作来自PBOO的动物模型（兔和小鼠）的平滑肌组织以及来自手术标本的人膀胱组织的资源。这些项目是，1：细胞外基质对梗阻反应的变化（Macarak），2：逼尿肌平滑肌重塑过程中细胞外基质和牵张对平滑肌表型表达的影响（DiSanto），3：细胞和分子 梗阻诱导的逼尿肌重塑中逼尿肌收缩和膀胱功能障碍的基础（Chacko），和4 A&B：出口梗阻后膀胱重塑中跨桥循环和力产生和维持的调节机制（莫兰& Barsotti）。此外，我们还有两个核心，一个是膀胱组织核心（Zderic），一个是行政核心（Chacko & Wein），还有两个试点和可行性项目。这些是1）通过环孢菌素（Zderic）抑制钙神经氨酸途径减少出口梗阻中的逼尿肌肥大和（2）膀胱梗阻期间磷脂酶激活（LaBelle）。新提案 将确定哪些信号转导途径导致Ca 2+敏感，肌动蛋白-肌球蛋白相互作用，横桥循环，以及它们如何在重塑逼尿肌中改变。此外，它将有助于确定哪些变化在梗阻去除后是可逆的，以及哪些分子事件在膀胱中是不可逆的，即使在梗阻逆转后仍继续功能失调。来自这些研究的数据将有助于阐明PBOO后逼尿肌收缩力改变的细胞/分子基础，以鉴定可用于确定哪种梗阻性膀胱重塑超过收缩功能障碍不可逆的点的分子标志物，并靶向开发治疗的分子步骤。

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.