CELL SIGNALING IN BLADDER HYPERTROPHY

描述(摘自申请者的摘要)：人体膀胱壁 通过细胞成分的变化来应对增加的尿路抵抗力， 通常被认为是肥厚性的平滑肌质量增加以及 膀胱组织结构的重塑。这些组织学变化 伴随着功能变化，如残余尿量增加，膀胱 容量和排尿压力。膀胱肥大是一种进行性的 对以下几种情况引起的尿路出口梗阻的反应 由于男性良性前列腺增生症(BPH)，与年龄相关的膀胱功能障碍 在女性中，以及先天性泌尿生殖道畸形。BPH症状，很多 现在可以归因于膀胱功能障碍，出现在超过 60岁以上的男性有40%。 我们小组最近积累了一些独立的证据 肝素结合的表皮生长因子样生长因子(HB-EGF)，以及 至少两个ErbB家族受体能够从HD-EGF下游发出信号 (ErbB1和ErbB2)参与膀胱细胞对机械刺激的反应 刺激物。我们建议使用机械细胞拉伸的体外模型，并且 建立完全性和部分性膀胱出口梗阻的活体模型 假设：1)机械力激活多个信号系统 在膀胱细胞中；2)这些途径中的一个或多个是生长所必需的 对机械信号的反应；以及3)这些信号通路可以 以改变膀胱对出口梗阻的反应的方式进行操作 尿路。具体目的是：1)确定膀胱细胞 机械刺激引起的生长依赖于ERK-MAPK的激活， JNK/SAPK或p38MAPK的磷酸化级联作用。2)确定是否 机械刺激引起的膀胱细胞生长依赖于ErbB受体 配体和/或ErbB家族受体。 这些研究的动机是需要更新的治疗策略 阻塞性疾病，基于更透彻的理解的治疗 膀胱对尿液出口的反应的基本病理生理学 障碍物。基于梗阻潜在机制的新疗法 尿路疗法将减少手术干预的需要，并改善 非恶性膀胱功能障碍患者的生活质量。

DESCRIPTION (Adapted from the Applicant's Abstract): The human bladder wall responds to increased urethral resistance by changes in cellular composition, generally seen as a hypertrophic increase in smooth muscle mass as well as remodeling of the bladder tissue architecture. These histologic changes accompany functional changes such as increases in residual urine, bladder volume, and voiding pressure. Bladder hypertrophy occurs as a progressive response to urinary outlet obstruction resulting from several conditions, such as benign prostatic hyperplasia (BPH) in men, age-related bladder dysfunction in women, as well as congenital urogenital tract anomalies. BPH symptoms, many of which can now be attributed to bladder dysfunction, arise in greater than 40% of men over the age of 60. Our group has recently accumulated a number of independent lines of evidence that heparin-binding epidermal growth factor-like growth factor (HB-EGF), and at least two ErbB family receptors capable of signaling down-stream from HD-EGF (ErbB1 and ErbB2), are involved in the response of bladder cells to mechanical stimuli. We propose to use an in vitro model of mechanical cell stretch, and in vivo models of complete and partial bladder outlet obstruction, to test the hypothesis that: 1) mechanical forces activate multiple signaling systems in bladder cells; 2) one or more of these pathways is required for a growth response to mechanical signals; and 3) these signaling pathways can be manipulated in ways that alter the bladder's response to outlet obstruction of the urinary tract. The Specific Aims are: 1) To determine whether bladder cell growth evoked by mechanical stimuli is dependent on activation of the ERK-MAPK, JNK/SAPK or the p38 MAPK phosphorylation cascades. 2) To determine whether bladder cell growth evoked by mechanical stimuli is dependent on ErbB receptor ligands and/or ErbB family receptors. These studies are motivated by a need for newer treatment strategies for obstructive disease, therapies which are based on a more thorough understanding of the underlying pathophysiology of the bladder's response to urinary outlet obstruction. New therapies based on the underlying mechanisms of obstructive uropathy will diminish the need for surgical intervention and improve the quality of life for patients with non-malignant bladder dysfunction.