MOLECULAR PATHWAY TO BLADDER DYSFUNCTION

描述（改编自申请人摘要）：良性前列腺 增生是一种慢性衰弱人类状况， 老年人 这种疾病与一种异常的进行性良性 在中年开始的前列腺的过度生长。 这 异常的前列腺生长增加膀胱出口的阻力， 随着时间的推移，导致膀胱质量，组织成分， 容量、依从性和对药理学试剂的反应。 过去 6年来，罗伯特·莱文和拉尔夫·巴廷的实验室 合作研究部分膀胱出口的动物模型 梗阻 这项合作产生了一系列科学成果， 我们认为，这些出版物描述了一些重要的遗传成分， 与膀胱功能障碍的形成有直接关系 这些 研究使我们假设， 部分出口阻塞是引发的潜在刺激， 膀胱的变化进展，最终导致膀胱 功能障碍 我们提出的研究将检验这一假设， 旨在确定控制细胞/遗传机制， 部分阻塞的兔膀胱通过3个不同的 最终导致严重膀胱功能障碍的发展阶段 这与在人类BPH中观察到的相似。 具体而言，1. 我们将 确定过度扩张是否是膀胱增大的先决条件 质量，收缩功能障碍，和遗传反应期间观察到的 部分出口阻塞后的初期。 2. 我们将确定 结束膀胱对部分膀胱癌的第一阶段反应的遗传信号， 出口梗阻（肥大），并开始进入第二个 膀胱反应阶段（补偿）。 3. 我们将密切关注 与部分膀胱出口梗阻相关的缺氧。 我们还 将测定部分阻塞的兔膀胱中是否存在 缺血的遗传和其他分子标记。 4. 我们会直接 比较遗传反应的序列和特征， 出口梗阻伴急性发作性利尿。 急性发作性利尿 导致膀胱质量显著增加， 对各种刺激的收缩反应。

DESCRIPTION (Adapted from the Applicant's Abstract): Benign prostatic hyperplasia is chronic an debilitation human condition that is common in aging men. The disease is associated with an abnormal progressive benign overgrowth of the prostate gland that is initiated in middle age. This abnormal prostate growth increases the resistance of the bladder outlet and over time, leads to major alterations in bladder mass, tissue composition, capacity, compliance, and response to pharmacological agents. Over the past 6 years, the laboratories of Robert Levin and Ralph Buttyan have collaborated in the study of animal models of partial bladder outlet obstruction. This collaboration has resulted in a series of scientific publications that describe some important genetic components that we believe are directly involved in the development of a dysfunctional bladder. These studies have led to our hypothesis that bladder ischemia subsequent to partial outlet obstruction is the underlying stimulus for the initiation and progression of changes in the bladder that ultimately results in bladder dysfunction. Our proposed studies will test this hypothesis, and are directed at identifying the cellular/genetic mechanisms that control the transition of the partially obstructed rabbit bladder through 3 distinct phases ultimately leading to the development of severe bladder dysfunctions similar to those observed with human BPH. Specifically, 1. We will determine if overdistension is a prerequisite for the increase in bladder mass, contractile dysfunctions, and genetic responses observed during the initial period following partial outlet obstruction. 2. We will identify the genetic signals that end the first phase of bladder response to partial outlet obstruction (hypertrophy) and initiate the entry into the second phase of bladder response (compensation). 3. We will monitor the extent of hypoxia associated with partial bladder outlet obstruction. As well, we will assay the partially obstructed rabbit bladder for the presence of genetic and other molecular markers of ischemia. 4. We will directly compare the sequence and characteristics of the genetic response to partial outlet obstruction with that of acute onset diuresis. Acute onset diuresis results in a significant increase in bladder mass with increases in the contractile responses to all forms of stimulation.