Regulation of Transepithelial Transport in PKD

PKD 中跨上皮转运的调节

基本信息

批准号：
7391310
负责人：
RAJEEV ROHATGI
金额：
$ 12.77万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391310
关键词：
Address Adolescence Affect Age Apical Appendix Attention Autosomal Dominant Polycystic Kidney Autosomal Recessive Polycystic Kidney Biological Assay Birth Cell Line Cells Chronic Kidney Failure Cilia Cyst Cyst Fluid Data Development Disease Duct (organ) structure Elevation End stage renal failure Epidermal Growth Factor Receptor Epithelial Cells Epithelium Fluids and Secretions Fluorescence Foundations Genes Growth Hereditary Disease Human Human Genetics Hypertension Immunoblotting Immunoprecipitation In Vitro Infant Ion Transport Kidney Kidney Diseases Kidney Failure Lead Life Light Live Birth Measurement Measures Mechanics Mediating Messenger RNA Mitogens Modeling Molecular Molecular Analysis Morbidity - disease rate Mus Mutation Nephrectomy Nephrons Pathway interactions Patients Perinatal Phosphatidylinositols Phospholipase C Polycystic Kidney Diseases Protein Tyrosine Kinase Proteins Rate Regulation Reporting Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Transduction Specimen Staging System Techniques Testing Tracer Tubular formation Urine absorption base disease characteristic early onset epithelial Na+ channel fetal human disease mortality patch clamp renal epithelium research study shear stress solute

项目摘要

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a common genetic human disease which is associated with a high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects approximately 1: 1,000 people while autosomal recessive PKD (ARPKD) affects approximately 1: 20,000 five births. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the sixth decade of life while most infants with ARPKD that survive beyond the perinatal period develop chronic renal failure by early adolescence. In PKD cyst growth and expansion destroys normal renal parenchyma and leads to renal failure. In ADPKD, cysts, which can arise from any tubular segment, "bud" off from the nephron and no longer communicate with the tubule from which they originate. In contrast, cysts in ARPKD are actually ectatic dilated collecting ducts which remain contiguous with the remaining nephron, allowing for urine to continue to flow through the dilated collecting system. Evidence from experimental ADPKD models and human disease suggests that cyst formation and expansion arise, at least in part, from transepithelial solute and fluid secretion. In contrast to the latter observation we have recently reported that ARPKD cyst lining epithelium, at least early in disease, is a Na absorptive epithelium. The rate limiting step in transepithelial Na absorption lies at the level of the apical epithelial Na channel (ENaC) and the steady state levels of the alpha and beta subunits of this channel are highly expressed in ARPKD cells. Based on these results we hypothesize that ARPKD is associated with upregulated Na absorption, presumably mediated by ENaC, which we speculate contributes to the early onset of hypertension. This hypothesis will be explored by answering the following specific aims and using a combination of molecular, electrophysiologic, and functional techniques: SAI: To identify the mechanism or pathway for Na absorption in ARPKD cystic epithelium. SA II: To identify those factors that regulate the avid Na absorption seen in ARPKD cyst lining epithelial cells.

描述（由申请人提供）：多囊肾病（PKD）是一种常见的人类遗传疾病，具有高发病率和死亡率。常染色体显性 PKD (ADPKD) 影响大约 1: 1,000 人，而常染色体隐性 PKD (ARPKD) 影响大约 1: 20,000 5 名新生儿。大约 50% 的 ADPKD 患者在 60 岁时发展为终末期肾病 (ESRD)，而大多数存活超过围产期的 ARPKD 婴儿在青春期早期发展为慢性肾功能衰竭。在 PKD 中，囊肿的生长和扩张会破坏正常的肾实质并导致肾功能衰竭。在 ADPKD 中，囊肿可以从任何肾小管节段产生，从肾单位“出芽”，不再与它们起源的肾小管连通。相比之下，ARPKD 中的囊肿实际上是扩张性扩张的集合管，它与剩余的肾单位保持连续，允许尿液继续流过扩张的集合系统。来自实验性 ADPKD 模型和人类疾病的证据表明，囊肿的形成和扩张至少部分是由跨上皮溶质和液体分泌引起的。与后一种观察相反，我们最近报道 ARPKD 囊肿内衬上皮，至少在疾病早期，是 Na 吸收性上皮。跨上皮 Na 吸收的速率限制步骤位于顶端上皮 Na 通道 (ENaC) 的水平，并且该通道的 α 和 β 亚基的稳态水平在 ARPKD 细胞中高度表达。基于这些结果，我们假设 ARPKD 与 Na 吸收上调有关，这可能是由 ENaC 介导的，我们推测这有助于高血压的早期发作。将通过回答以下具体目标并结合分子、电生理学和功能技术来探索这一假设： SAI：确定 ARPKD 囊性上皮吸收 Na 的机制或途径。 SA II：确定 ARPKD 囊肿内层上皮细胞中调节 Na 强烈吸收的因素。