Jade-1 in cystic renal disease

Jade-1 在囊性肾病中的作用

• 批准号: 7234711
• 负责人: HERBERT TOD COHEN
• 金额: $ 30.23万
• 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/7234711
• 关键词: Accounting; Acinus organ component; Anoikis; Apoptosis; Apoptotic; Autosomal Dominant Polycystic Kidney; Binding; Breast; Cell Adhesion; Cell Cycle; Cell Proliferation; Coiled-Coil Domain; Cyst; Cystic Kidney Diseases; Cystic kidney; Cytoplasmic Tail; Development; Disease; Dominant-Negative Mutation; Employee Strikes; End stage renal failure; Epithelial Cells; Epithelium; Genes; Genetic; Growth; Hereditary Disease; Kidney; Kidney Diseases; Laboratories; Life; Mediator of activation protein; Missense Mutation; Molecular; Morphology; Mutation; Nuclear; PKD2 protein; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphoproteins; Plants; Polycystic Kidney Diseases; Property; Protein Family; Proteins; Regulation; Regulatory Pathway; Renal tubule structure; Risk; Role; Tubular formation; Tumor Suppressor Proteins; Von Hippel-Lindau Syndrome; Zinc; base; disorder risk; homeodomain; interest; kidney cell; member; monolayer; novel; polycystic kidney disease 1 protein; prevent; transcription factor

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）是终末期肾病的常见原因。多囊蛋白-1-多囊蛋白-2相互作用的丧失是疾病发病机制的核心，但囊肿形成的确切机制仍不清楚。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（包括多囊肾表型）的分子基础。 VHL 疾病和 ADPKD 的囊肿途径之间存在惊人的相似性。 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，该转录因子由 VHL 肿瘤抑制因子稳定。 Jade-1 存在于显着的核斑点中，并且在肾小管上皮细胞中表达最高。有趣的是，稳定 Jade-1 的自然发生的 VHL 突变模式表明与 VHL 肾病风险存在相关性，而此前尚未对此进行过描述。 Jade-1 蛋白改变肾细胞的单层形态并促进被 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细胞，促进失巢凋亡。值得注意的是，野生型多囊蛋白-1 与 VHL 非常相似，强烈调节 Jade-1，并且这种效应被卷曲螺旋结构域中致病的多囊蛋白-1 突变所阻断，该突变阻止了与多囊蛋白-2 的相互作用。此外，Jade-1 是一种新型多囊蛋白-1 显性失活机制的靶标。因此，促凋亡 Jade-1 是 VHL 和常见多囊蛋白-1 / 多囊蛋白-2 调节途径的下游。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心调节因子。将通过以下目标探索 Jade-1 - 多囊蛋白在囊性疾病中的关系： 目的1：多囊蛋白1对Jade-1的调控机制 目标 2：Jade-1 对细胞周期的影响以及多囊蛋白-1 的调节 目标 3：Jade-1 在肾囊肿形成中的直接作用。