ALTERED COLLECTING TUBULE ION TRANSPORT IN ARPKD

描述：（直接从申请中获取）多囊肾病（PKD）在美国影响超过50万人，占所有接受透析或移植的终末期肾病患者的10%。该病的特点是形成多个充满液体的囊肿，破坏肾脏结构，损害正常肾功能。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改变、细胞增殖的增强和离子转运的改变。肾囊上皮分泌液体的能力和EGF受体过表达和错定位的重要性最近已经确立。本项目的总体目标是确定囊性上皮的离子转运表型，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中收集小管离子转运的影响。我们的工作假设是异常的egfr信号有助于增强细胞增殖，并揭示囊性上皮的分泌表型。将进行肾切片器官培养、原代单层培养和条件永生化囊性和非囊性收集小管细胞系的电生理研究。药理学和遗传学方法将用于评估囊性上皮中阿米洛利敏感的钠吸收、钡敏感的钾分泌和camp或钙激活的氯分泌的重要性。顶端和基底侧EFGR信号对特定离子运输途径的影响将被评估。我们期望我们在小鼠ARPKD上的发现将增强我们对PKD细胞病理生理的理解，并有助于设计常染色体隐性和常染色体显性人类PKD的治疗方法。

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.