Jade-1 in cystic renal disease

描述(申请人提供)：常染色体显性遗传性多囊肾病(ADPKD)是终末期肾脏疾病的常见原因。多囊蛋白-1-多囊蛋白-2相互作用的丧失是疾病发病机制的核心，但囊变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脏疾病的一致特征。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病和ADPKD的致囊途径有惊人的相似之处。JADE-1(上皮细胞凋亡和分化基因)编码一种短暂的、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位于显著的核斑点中，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肾脏疾病风险有关，这在以前还没有描述过。Jade-1蛋白改变了肾细胞的单层形态，促进了被VHL阻断的细胞凋亡。JADE-1可能有助于推动前凋亡的上皮细胞脱离单层，促进失巢凋亡。值得注意的是，野生型多囊蛋白-1像VHL一样强烈地调节JADE-1，这种作用被卷曲螺旋结构域中的致病多囊蛋白-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是一种新的多囊蛋白-1显性负机制的靶点。因此，促凋亡的JADE-1位于VHL和共同的多囊蛋白-1/多囊蛋白-2调控通路的下游。因此，JADE-1可能是VHL病和ADPKD以及其他囊性肾脏疾病中肾囊肿形成的中枢调节因子。我们将通过以下目的来探讨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 目的2：JADE-1对细胞周期的影响及多囊蛋白-1的调控作用 目的3：Jade-1在肾囊肿形成中的直接作用。

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.