MOLECULAR PATHWAY TO BLADDER DYSFUNCTION

描述(摘自申请者摘要)：良性前列腺 增生症是一种慢性衰弱的人类疾病，在 上了年纪的男人。这种疾病与一种异常的进行性良性疾病有关。 中年时开始的前列腺过度生长。这 异常的前列腺生长增加了膀胱出口的阻力， 随着时间的推移，会导致膀胱质量、组织成分、 能力、依从性和对药理药物的反应。在过去的时间里 6年来，罗伯特·莱文和拉尔夫·巴蒂安的实验室 合作研究部分膀胱出口的动物模型 障碍物。这种合作导致了一系列的科学研究 这些出版物描述了我们认为的一些重要的遗传成分 与膀胱功能障碍的发生有直接关系。这些 研究导致了我们的假设，即膀胱缺血后 部分出口阻塞是启动和恢复的潜在刺激。 膀胱变化的进展，最终导致膀胱 功能障碍。我们提议的研究将检验这一假设，并将 旨在确定控制细胞/遗传机制的 兔部分梗阻性膀胱经三种不同途径的移行 最终导致严重膀胱功能障碍的发展阶段 与人类前列腺增生症的观察结果相似。具体来说，1.我们将 确定过度膨胀是否是膀胱增多的先决条件 观察到的质量、收缩功能障碍和遗传反应 出口部分梗阻后的初期。2.我们将确定 结束膀胱部分反应第一阶段的遗传信号 出口梗阻(肥大)并开始进入第二个 膀胱反应时相(代偿期)。3.我们会监察 低氧合并部分膀胱出口梗阻。同样，我们 会检测部分梗阻的兔膀胱中是否存在 缺血的遗传和其他分子标志物。4.我们将直接 比较部分基因反应的序列和特征 出口梗阻伴急性起病利尿。急性发作性利尿 结果导致膀胱质量显著增加，其中 对各种形式的刺激的收缩反应。

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.