Pathophysiology of ARPKD: role of aberrant transport

ARPKD 的病理生理学：异常转运的作用

• 批准号: 6600747
• 负责人: Lisa M. Satlin
• 金额: $ 28.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6600747
• 关键词: SDS polyacrylamide gel electrophoresis; Xenopus oocyte; autosomal dominant trait; autosomal recessive trait; biological signal transduction; cell adhesion; cell proliferation; electrophysiology; extracellular matrix; hypertension; immunofluorescence technique; ion transport; laboratory rat; northern blottings; pathologic process; polycystic kidney; polymerase chain reaction; renal failure; renal tubule; secretion; tissue /cell culture; urinary incontinence; voltage /patch clamp; water channel; western blottings

The hereditary forms of polycystic kidney disease (PKD) include the common autosomal dominant form (ADPKD), affecting 1 in approximately 1000 of the population, and the less common autosomal recessive form (ARPKD), affecting 1 in approximately 20,000 live births. Both diseases are characterized by the formation and expansion of cysts derived from specific segments of the nephron. In ADPKD, the gradual destruction of normal renal parenchyma by cysts arising in multiple nephron segments lead to renal failure in approximately 50% of patients by the sixth decade of life. ARPKD, a disease with high infant morbidity, is characterized by the progressive dilatation of collecting ducts, the nephron segment responsible for the final renal regulation of Na, K, acid-base and water balance. Three mechanisms have been implicated in the process of cyst formation and expansion: cell proliferation, abnormal extracellular matrix and adhesion, and net transepithelial fluid. Whereas data exists to implicate the former two processes in the pathogenesis of ARPKD, little is known about the regulation of transepithelial solute and water transport in this disease. Our long term goal is to identify alterations in the expression and regulation of epithelial cell transport pathways that contribute not only to cyst expansion, but also the early onset of hypertension and polyuria in APRKD. The hypotheses we propose to examine in this 5-year application are focused on (I) characterizing the molecular and functional expression of ion channels, transporters, and receptors, and (II, III) exploring the mechanisms by which aberrant autocrine/paracrine signaling and/or cellular responses to biomechanical forces lead to dysregulated transepithelial transport in ARPKD collecting dust cysts. To best understand the pathogenesis of human disease, we propose to perform most studies described in this application in immortalized principal cell lines derived from human ARPKD collecting duct cysts or age-matched normal human kidney (NHK). Parallel studies will also be performed in the orpk murine model of ARPKD, whose microdissected tubules can be isolated and microperfused in vitro.

多囊肾病 (PKD) 的遗传形式包括常见的常染色体显性形式 (ADPKD)，影响大约千分之一的人口，以及不太常见的常染色体隐性形式 (ARPKD)，影响大约两万分之一的活产儿。这两种疾病的特征都是来自肾单位特定部分的囊肿的形成和扩张。在 ADPKD 中，多个肾单位节段中出现的囊肿逐渐破坏正常肾实质，导致大约 50% 的患者到 60 岁时出现肾功能衰竭。 ARPKD 是一种婴儿发病率较高的疾病，其特征是集合管进行性扩张，肾单位负责钠、钾、酸碱和水平衡的最终肾脏调节。囊肿形成和扩张过程涉及三种机制：细胞增殖、异常细胞外基质和粘附以及净跨上皮液。尽管现有数据表明 ARPKD 发病机制中的前两个过程有关，但对该疾病中跨上皮溶质和水转运的调节知之甚少。我们的长期目标是确定上皮细胞转运途径表达和调节的变化，这些变化不仅有助于囊肿扩张，而且有助于 APRKD 中高血压和多尿的早期发作。我们建议在这项为期 5 年的申请中研究的假设重点是 (I) 表征离子通道、转运蛋白和受体的分子和功能表达，以及 (II、III) 探索异常自分泌/旁分泌信号传导和/或细胞对生物力学力的反应导致 ARPKD 收集尘囊的跨上皮运输失调。为了更好地了解人类疾病的发病机制，我们建议在源自人 ARPKD 集合管囊肿或年龄匹配的正常人肾脏 (NHK) 的永生化主要细胞系中进行本申请中描述的大多数研究。平行研究还将在 ARPKD 的 orpk 小鼠模型中进行，该模型的显微解剖肾小管可以在体外分离和微灌注。