MOLECULAR RESPONSE OF THE BLADDER TO OBSTRUCTION

描述(摘自申请者摘要)：膀胱肌 正常的膀胱需要胎儿期的伸展和放松 发展。缺乏足够水平的机械性运动或 体量工作或破坏正常的伸展模式 膀胱壁会导致体内生化和结构的改变 最终影响膀胱的膀胱肌肉和结构蛋白 功能。大多数胎儿的应激状态与 发生在发育过程中的泌尿生殖系统病变，如后遗症 继发性功能性膀胱梗阻的尿道瓣 脊髓脊膜膨出和羊水过少会影响肺部发育。 本研究的目的是：1)建立大鼠脑缺血再灌注损伤动物模型 胎儿膀胱梗阻及逆转的手术疗效 干预措施，2)确定机械信号的作用，即 Stretch，在调节细胞外基质的合成和积累中 在胚胎绵羊模型的发育过程中；3)测定 发育中的膀胱对基质和生长的物理阻碍 因子表达(即刻早期基因和转化生长因子-β、碱性成纤维细胞生长因子、神经生长因子)； 4)测定基质和生长因子的参数和动力学 梗阻逆转后的表达；5)确定是否拉伸， 在没有梗阻引起的高压的情况下(膀胱切开术 模型)，或缺乏拉伸和容量做功(双侧肾切除术) 允许膀胱重塑并维持其自身作为一个功能器官 6)确定转录因子Wilms的作用 肿瘤基因产物(wt-1)在膀胱发育调控中的作用 阻碍和反转。膀胱功能的生理学测量 将通过膀胱测定法来确定。眼球运动图将被关联 通过纵向分析细胞外基质稳态mRNA和 蛋白质表达(氨基酸分析、桥联蛋白分析、ELISA)以 评估激活或抑制的动力学，组织学和 免疫组织化学分析确定这些蛋白的定位 在开发过程中以及因障碍物而造成的任何改变。 将进行电子显微镜检查，以确定胶原原纤维 直径发生变化，并与ThpeIII：类型I的变化相关 胶原蛋白定量和功能生理顺应性测量。

DESCRIPTION (Adapted from the Applicant's Abstract): Bladder muscle stretch and relaxation during fetal life are required for normal bladder development. A lack of an adequate level of mechanical exercise or volume work or a disruption of the normal patterns of stretch within the bladder wall will lead to biochemical and structural alterations within the bladder muscle and structural proteins ultimately affecting bladder function. The majority of fetal stress conditions are related to urogenital pathologies which occur developmentally, such as posterior urethral valves, functional bladder obstructions secondary to myelomeningocele and oligohydramnios which can affect lung development. The objectives of this study are: 1) to establish an animal model of fetal bladder obstruction and reversal, and the efficacy of surgical interventions, 2) to determine the role of mechanical signals, i.e. stretch, in regulating extracellular matrix synthesis and accumulation in the developing fetal sheep model; 3) to determine the effect of physical obstruction of the developing bladder on matrix and growth factor expression (immediate early genes and TGF-betas, basic FGF, NGF); 4) to determine the parameters and kinetics of matrix and growth factor expression following obstruction reversal; 5) to determine if stretch, in the absence of high pressures induced by obstruction (vesicotomy model), or absence of stretch and volume-work (bilateral nephrectomy) allows the bladder to remodel and maintain itself as a functional organ and 6) to determine the role of the transcription factor, the Wilms tumor gene product (wt-1) in the regulation of bladder development, obstruction and reversal. Physiological measurements of bladder function will be determined by cystometry. Cystometrograms will be correlated with longitudinal analyses of extracellular matrix steady state mRNA and protein expression (amino acid analyses, desmosine analysis ELISA) to evaluate the kinetics of activation or repression, histological and immunohistochemical analyses to determine localization of these proteins during development and any alteration as a result of obstruction. Electron microscopy will be performed to determine if collagen fibril diameter is altered and correlated with changes in thpeIII:type I collagen rations and functional physiologic compliance measurements.