Univ of Maryland Baltimore Interdisciplinary Research Center in Benign Urology

描述(申请人提供)：OAB的病理生理学尚不清楚。虽然目前已提出的病因包括逼尿肌平滑肌和神经机制，但膀胱尿路上皮细胞(BUC)在OAB中的潜在作用是一个新的探索途径。马里兰大学良性泌尿外科跨学科研究中心(UM-IRC)将进行一项计划研究，从无尿失禁和无排尿症状的受试者(对照组)和有OAB症状的受试者(急迫性尿失禁)进行膀胱尿路上皮活检。来自这些活检组织的原代BUC培养将在项目主任(Chai)和两名联合首席研究员(Birder，Keay)的实验室进行研究。由于这些实验室已经有了独立的资金，UM-IRC采用了多重PI方法。实验室研究的目的是获得初步的实验室数据，然后使用实验室客观测量作为主要结果，帮助从统计上支持下一次OAB试验。将测量的BUC的三种表型是细胞内多胺的表达，紧密连接蛋白的表达，以及通过释放三磷酸腺苷(ATP)来衡量细胞对低渗和化学刺激的机械敏感性。早期的初步数据表明，OAB BUC的所有这三种表型都发生了变化。在这一规划阶段，UM-IRC将坚定地在三个实验室之间建立合作，这三个实验室已经活跃在基础膀胱尿路上皮生物学研究中。在规划阶段，将使用一个咨询小组来管理UM-IRC。由于头两年最重要的因素是招募OAB和对照受试者接受膀胱尿路上皮活检，咨询小组除了受试者的安全性外，还将持续监测招募人数。UM-IRC将利用马里兰大学大陆和骨盆中心进行招募。目前有几个OAB临床试验正在进行中，这可以帮助这一提议的招募。根据RFA的预算限制，将招收10个OAB和10个控制科目。UM-IRC将利用跨学科的方法进行将尿路上皮病理生理学与OAB联系起来的转换研究。 公共卫生相关性：膀胱过度活动(OAB)是一种高度流行的疾病，在美国有1600多万人受到影响。OAB的诊断和治疗仍处于初级阶段，几乎完全依赖患者报告的症状。通过基础科学实验增加对这种情况的认识，我们希望了解OAB的原因。具体地说，我们将重点介绍膀胱衬里细胞(尿路上皮细胞)在OAB病因中的作用。

DESCRIPTION (provided by applicant): The pathophysiology of OAB is unknown. While there are proposed etiologies including detrusor smooth muscle and neural mechanisms, the potential contribution of the bladder urothelial cells (BUC) to OAB is a new avenue of inquiry. The University of Maryland Interdisciplinary Research Center (UM-IRC) in benign urology will perform a planning study in which bladder urothelial biopsies will be obtained from subjects with no urinary incontinence and no voiding symptoms (controls) and from subjects with OAB symptoms (urge incontinence). Primary BUC cultures derived from these biopsies will be studied in the laboratories of the Program Director (Chai) and the two co-principal investigators (Birder, Keay). Because these labs already have independent funding, the multiple PI approach for the UM-IRC is utilized. The intent of the laboratory studies Is to obtain preliminary laboratory data which then can help statistically power the next OAB trial using laboratory objective measures as primary outcomes. The three phenotypes of BUC that will be measured are expression of intracellular polyamines, expression of tight junction proteins, and cellular mechanosensitivity measured by adenosine triphosphate (ATP) release in response to hypo-osmotic and chemical stimuli. Early preliminary data suggest alterations in all three of these phenotypes in OAB BUC. During this planning phase, the UM-IRC will firmly establish collaboration among the three laboratories which are already active in basic bladder urothelial biologic studies. An advisory panel will be used to govern the UM-IRC during the planning phase. Because the most important factor during the first two year is recruitment of OAB and control subjects to undergo bladder urothelial biopsies, the advisory panel will maintain constant surveillance of the recruitment numbers in addition to subject safety. The UM-IRC will utilize the Univ of Maryland Continence and Pelvic Center for recruitment. There are several OAB clinical trials currently ongoing which can help with the recruitment for this proposal. Based on the budgetary constraints of the RFA, 10 OAB and 10 control subjects will be enrolled. The UM-IRC will utilize an interdisciplinary approach in performing translational research linking urothelial pathophysiology to OAB. PUBLIC HEALTH RELEVANCE: Overactive bladder (OAB) is a highly prevalent condition affecting over 16 million people in the USA. Diagnosis and treatment for OAB remains rudimentary and rely almost exclusively on patient reported symptoms. By increasing the understanding of this condition with basic science experiments, we hope to understand the causes for OAB. Specifically we will focus on the role of the bladder lining cells (urothelial CRIIS) in the cause of OAB.