Molecular Basis of Bladder Organogenesis

膀胱器官发生的分子基础

• 批准号: 6857899
• 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/6857899
• 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%的人类婴儿出生时就患有某种形式的泌尿生殖系统异常，其中很大一部分婴儿涉及膀胱。膀胱结构和/或功能的异常会导致严重的发病率，包括感染、大小便失禁甚至肾功能不全。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。器官发生需要有序地执行调控时间和空间上确定的细胞分化和增殖的程序。令人惊讶的是，人们对正常膀胱器官发生过程中发生的事件知之甚少。这在一定程度上是因为缺乏合适的实验动物模型来研究胎儿膀胱的发育。 这项建议的长期目标是以非洲爪哇为实验系统，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哇是这一提议的理想模型，因为膀胱在幼虫阶段发育，并且很容易接近。此外，我们还发现Uroplakin家族基因在胚胎发育和膀胱器官发育过程中很早就有表达。这一点很重要，因为尿路上皮细胞长期以来一直被认为是尿路上皮终末分化的标志。本研究旨在扩大我们对膀胱器官发生的分子调控以及Uroplakin在这一发育过程中的作用的理解，其具体目的如下：(1)鉴定与膀胱器官发生相关的基因；(2)研究特定目标1中确定的基因调控膀胱器官发生的机制(S)；(3)确定Uroplakin基因在早期胚胎发生和膀胱器官发生中的功能。通过这些研究，候选人将描绘出调控膀胱器官发生的信号转导途径。这项提议的结果将大大拓宽我们对膀胱发育、生长、再生和对损伤的反应的洞察力。这些知识将被用来加强目前治疗干预的结果，并改善先天性或获得性膀胱功能障碍患者的生活质量。