ALTERED COLLECTING TUBULE ION TRANSPORT IN ARPKD

ARPKD 中收集管离子传输的改变

• 批准号: 6493082
• 负责人: CALVIN U COTTON
• 金额: $ 16.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493082
• 关键词: autosomal recessive trait; biological signal transduction; cell line; disease /disorder model; electrophysiology; epidermal growth factor; epithelium; gene targeting; genetically modified animals; growth factor receptors; ion transport; kidney pharmacology; laboratory mouse; membrane channels; microelectrodes; organ culture; phenotype; polycystic kidney; renal tubular transport

Description: (Taken directly from the application) Polycystic kidney diseases (PKD) affect more than 500,000 people in the United States and are responsible for 10% of all patients receiving dialysis or transplantation for end-stage renal disease. The disease is characterized by the formation of multiple fluid-filled cysts that disrupt renal architecture and compromise normal renal function. Autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD) are genetic diseases caused by mutations in three known genes and several yet to be identified genes. The functions of the gene products are not known. It is widely accepted that there are changes in extracellular matrix, enhanced cell proliferation, and alterations in ion transport that accompany and/or drive cyst formation. The capacity of renal cystic epithelium to secrete fluid and the importance of EGF receptor overexpression and mislocalization have recently been established. The overall objective of this project to is to identify the ion transport phenotype of cystic epithelium, to establish the importance of C1 and fluid secretion in cyst expansion, and to determine the effect of EGFR signaling on collecting tubule ion transport in ARPKD. Our working hypothesis is that abnormal EGFR-signaling contributes to enhanced cell proliferation and unmasks a secretory phenotype in cystic epithelia. Electrophysiologic studies of renal slice organ culture, primary monolayer culture, and conditionally-immortalized cystic and non-cystic collecting tubule cell lines will be conducted. A pharmacologic and genetic approach will be used to evaluate the importance of amiloride-sensitive sodium absorption, barium-sensitive potassium secretion, and cAMP-or calcium-activated chloride secretion in cystic epithelia. The effect of apical and basolateral EFGR signaling on specific ion transport pathways will be evaluated. We anticipate that our findings with murine ARPKD will enhance our understanding of PKD cellular pathophysiology and contribute to the design of therapies for both autosomal recessive and autosomal dominant human PKD.

产品描述：多囊肾病（PKD）在美国影响超过50万人，占所有因终末期肾病接受透析或移植的患者的10%。这种疾病的特征是形成多个充满液体的囊肿，破坏肾脏结构并损害正常的肾功能。常染色体显性PKD（ADPKD）和常染色体隐性PKD（ARPKD）是由三个已知基因和几个尚未确定的基因突变引起的遗传性疾病。基因产物的功能尚不清楚。人们普遍认为，伴随和/或驱动囊肿形成的是细胞外基质的变化、细胞增殖的增强以及离子转运的改变。肾囊性上皮细胞分泌液体的能力和EGF受体过表达和错误定位的重要性最近已经确定。本项目的总体目标是确定囊性上皮细胞的离子转运表型，确定C1和液体分泌在囊肿扩张中的重要性，并确定EGFR信号传导对ARPKD中集合管离子转运的影响。我们的工作假设是，异常的EGFR信号有助于增强细胞增殖，并揭示了囊性上皮细胞的分泌表型。将对肾切片器官培养、原代单层培养以及条件永生化囊性和非囊性集合小管细胞系进行电生理学研究。将使用药理学和遗传学方法来评价阿米洛利敏感的钠吸收、钡敏感的钾分泌和cAMP或钙激活的氯分泌在囊性上皮中的重要性。将评价顶侧和基底侧EFGR信号传导对特定离子转运途径的影响。我们预计，我们的研究结果与鼠ARPKD将提高我们的PKD细胞病理生理学的理解，并有助于设计治疗常染色体隐性和常染色体显性人类PKD。