Molecular Basis of Bladder Organogenesis

膀胱器官发生的分子基础

• 批准号: 7012226
• 负责人: PRAMOD P REDDY
• 金额: $ 12.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012226
• 关键词: Xenopus; Xenopus oocyte; biological models; biological signal transduction; cell differentiation; cell proliferation; developmental genetics; embryogenesis; endoderm; gene expression; genetically modified animals; histogenesis; membrane proteins; mesoderm; microarray technology; molecular biology; urinary bladder; urinary bladder epithelium

DESCRIPTION (provided by applicant): Up to 1% of all human infants are born with some form of genitourinary abnormality, with a large proportion of them having involvement of the urinary bladder. Abnormal structure and/or function of the bladder results in significant morbidity, including infections, incontinence and even renal insufficiency. Because of its clinical significance, we have begun to study the molecular basis of organogenesis of the urinary bladder. Organogenesis requires the orderly execution of programs that regulate temporally and spatially defined cellular differentiation and proliferation. Surprisingly very little is actually known about the events that occur during normal bladder organogenesis. This is in part due to the lack of an appropriate experimental animal model with which to study the development of the fetal bladder. The long term goal of this proposal is to elucidate the molecular basis of urinary bladder organogenesis in vertebrates, using Xenopus as an experimental system. In our preliminary experiments, we have demonstrated that Xenopus is an ideal model for this proposal since the urinary bladder develops in the larval stage and can be readily accessed. Additionally, we have discovered that the Uroplakin family of genes is expressed very early in embryogenesis and bladder organogenesis. This is significant because Uroplakins have long been considered markers of terminal urothelial differentiation. This proposal seeks to extend our understanding of the molecular regulation of bladder organogenesis, and the role that Uroplakin plays in this developmental pathway with the following specific aims: (1) Identify and characterize the genes involved in bladder organogenesis; (2) Examine the mechanism(s) by which the genes identified in specific aim 1 regulate bladder organogenesis; (3) To determine the function of the Uroplakin genes in early embryogenesis and bladder organogenesis. Through these studies, the candidate will delineate the signal transduction pathways that regulate bladder organogenesis. The results of this proposal will significantly broaden our insights into bladder development, growth, regeneration and response to injury. This knowledge will be utilized to enhance the outcomes of current therapeutic interventions and improve the quality of life for patients with congenital or acquired bladder dysfunction.

描述（由申请人提供）： 高达1%的人类婴儿出生时患有某种形式的泌尿生殖系统异常，其中很大一部分涉及膀胱。膀胱的异常结构和/或功能导致显著的发病率，包括感染、失禁和甚至肾功能不全。由于其临床意义，我们已经开始研究膀胱器官发生的分子基础。器官发生需要有序执行程序，调节时间和空间定义的细胞分化和增殖。令人惊讶的是，实际上很少有人知道正常膀胱器官发生过程中发生的事件。这部分是由于缺乏适当的实验动物模型来研究胎儿膀胱的发育。 本研究的长期目标是以非洲爪蟾为实验系统，阐明脊椎动物膀胱器官发生的分子基础。在我们的初步实验中，我们已经证明，非洲爪蟾是一个理想的模型，因为膀胱发育在幼虫阶段，可以很容易地访问。此外，我们发现Uroplakin家族基因在胚胎发生和膀胱器官发生的早期就表达。这是重要的，因为尿斑蛋白长期以来被认为是终末尿路上皮分化的标志物。本研究的目的是扩展我们对膀胱器官发生的分子调控以及尿斑蛋白在这一发育途径中所起作用的理解，具体目标如下：（1）鉴定和表征参与膀胱器官发生的基因;（2）研究具体目标1中鉴定的基因调控膀胱器官发生的机制;（3）研究Uroplakin基因在胚胎发育和膀胱器官发生中的作用。通过这些研究，候选人将描绘调控膀胱器官发生的信号转导途径。该提案的结果将显着拓宽我们对膀胱发育，生长，再生和对损伤的反应的见解。这些知识将被用来提高目前的治疗干预的结果，并改善先天性或后天性膀胱功能障碍患者的生活质量。