Jade-1 in cystic renal disease

Jade-1 在囊性肾病中的作用

• 批准号: 7049325
• 负责人: HERBERT TOD COHEN
• 金额: $ 31.13万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049325
• 关键词: MDCK cell; Von Hippel Lindau syndrome; apoptosis; cell cycle; cell differentiation; clinical research; cytogenetics; genetic regulation; genetically modified animals; human tissue; immunofluorescence technique; laboratory mouse; laboratory rat; polycystic kidney; polymerase chain reaction; protein structure function; urinary bladder epithelium; western blottings

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease. Loss of the polycystin-1 - polycystin-2 interaction is central to disease pathogenesis, but the precise mechanism of cyst formation remains unclear. Intriguingly, disordered renal tubule cell proliferation and apoptosis are consistent features of all the cystic renal diseases. Our laboratory has been closely studying the molecular basis of von HippeI-Lindau (VHL) renal disease, which includes a polycystic kidney phenotype. The similarities between the cystogenic pathways in VHL disease and ADPKD are striking. Jade-1 (gene for Apoptosis and Differentiation in Epithelia) encodes a short-lived, highly-regulated pro-apoptotic transcription factor that is stabilized by the VHL tumor suppressor. Jade-1 resides in prominent nuclear speckles and is most highly expressed in renal tubular epithelial cells. Intriguingly, the pattern of naturally occurring VHL mutations that stabilize Jade-1 suggest a correlation with VHL renal disease risk, which has not been previously described. Jade-1 protein alters the monolayer morphology of renal cells and promotes apoptosis that is blocked by VHL. Jade-1 may help propel a pre-apoptotic epithelial cell off a monolayer, promoting anoikis. Remarkably, wild-type polycystin-1 strongly regulates Jade-1 much like VHL, and this effect is blocked by a disease-causing polycystin-1 mutation in the coiled-coil domain that prevents interaction with polycystin-2. Moreover, Jade-1 is the target of a novel polycystin-1 dominant-negative mechanism. Thus, pro-apoptotic Jade-1 is downstream of both VHL and a common polycystin-1 / polycystin-2 regulatory pathway. Jade-1 may therefore be a central regulator of renal cyst formation in VHL disease and ADPKD, and perhaps in other cystic renal diseases. The Jade-1 - polycystin relationship in cystic disease will be explored through the following Aims: AIM 1: The mechanism of Jade-1 regulation by polycystin-1 AIM 2:Jade-1 effects on the cell cycle and modulation by polycystin-1 AIM 3: Direct role of Jade-1 in renal cyst formation.

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是终末期肾脏疾病的常见原因。多囊蛋白-1 -多囊蛋白-2相互作用的缺失是疾病发病机制的核心，但囊肿形成的确切机制尚不清楚。有趣的是，肾小管细胞增殖和凋亡紊乱是所有囊性肾病的一致特征。我们的实验室一直在密切研究von HippeI-Lindau （VHL）肾病的分子基础，其中包括多囊肾表型。VHL疾病和ADPKD的囊形成途径之间的相似性是惊人的。Jade-1（上皮细胞凋亡和分化基因）编码一种短寿命、高度调控的促凋亡转录因子，该因子被VHL肿瘤抑制因子稳定。Jade-1存在于突出的核斑中，在肾小管上皮细胞中表达最多。有趣的是，稳定Jade-1的自然发生的VHL突变模式表明与VHL肾脏疾病风险相关，这在以前没有被描述过。Jade-1蛋白改变肾细胞的单层形态，促进VHL阻断的细胞凋亡。Jade-1可能有助于推动凋亡前上皮细胞脱离单层，促进凋亡。值得注意的是，野生型多囊蛋白-1强烈调节Jade-1，就像VHL一样，这种作用被卷曲结构域的致病多囊蛋白-1突变阻断，该突变阻止了与多囊蛋白-2的相互作用。此外，Jade-1是一种新的多囊蛋白-1显性-负机制的靶标。因此，促凋亡的Jade-1位于VHL和常见的多囊蛋白-1 /多囊蛋白-2调控通路的下游。因此，Jade-1可能是VHL疾病和ADPKD以及其他囊性肾病中肾囊肿形成的中枢调节因子。Jade-1 - polycystin在囊性疾病中的关系将通过以下目的进行探讨：