权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Autosomal dominant polycystic kidney disease (ADPKD): The role of Aurora kinase A (AURKA), NEDD9 and SRC in renal cystogenesis

常染色体显性多囊肾病 (ADPKD)：极光激酶 A (AURKA)、NEDD9 和 SRC 在肾囊肿发生中的作用

基本信息

批准号：
226929403
负责人：
Dr. Tamina Seeger-Nukpezah
金额：
--
依托单位：
Institute for Cancer Research (aufgelöst)
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/226929403?language=en
关键词：
Autosomal dominant polycystic kidney disease

项目摘要

Autosomal dominant polycystic kidney disease (ADPKD) affects between 1:400 and 1:1000 individuals worldwide and typically manifests in middle age, with affected individuals progressing towards end stage renal disease. To date no specific treatment has been proven to prevent or delay ADPKD, although there are a number of emerging treatment strategies in PKD, currently in preclinical or clinical testing. ADPKD arises from mutations in PKD1 (~85% of cases) or PKD2 (~15% of cases) encoding polycystin-1 (PC1) and polycystin-2 (PC2). Their impaired function typically results in reduced intracellular Ca2+ pools, altered cell signaling by PC1- and PC2-interacting and effector proteins, loss of epithelial cell polarity, and deregulated renal cell growth. Beyond mutations in the PKD1 and PKD2 genes, mutations causing loss of primary cilia, which induces defects in sensing of external mechanosensory and soluble cues, again deregulating renal cell growth. Recently, important roles for AURKA, NEDD9 and SRC as regulators of ciliary integrity, PC2 activity, intracellular Ca2+ responses, and additional signaling relevant to ADPKD pathology has been established. In the described project the hypothesis will be tested that 1) abnormal function of AURKA, NEDD9 and SRC are linked and common in cystogenesis, and 2) targeted therapies focused on AURKA and SRC may have value in PKD contingent on NEDD9 status. Therefore the effect of a Nedd9-/- genotype on cystogenesis in mouse models for the conditional ablation of Pkd1 and Pkd2 will be analyzed. Further the interactions between NEDD9, AURKA, and SRC in signaling pathways relevant to cystogenesis will be dissected in renal cell lines and finally AURKA inhibitors in restricting cyst formation will be evaluated. The overall goal of this proposal is to better understand the interrelated functions of NEDD9 and its interaction partners AURKA and SRC kinase, both as a way of yielding fundamental insight into basic biology of PKD, and with the goal of suggesting new and accessible therapeutic strategies.

常染色体显性遗传性多囊肾病（ADPKD）影响全球1：400至1：1000的个体，通常在中年表现，受影响的个体进展为终末期肾病。到目前为止，还没有具体的治疗方法被证明可以预防或延迟ADPKD，尽管有一些正在出现的PKD治疗策略，目前正在进行临床前或临床试验。ADPKD由编码多囊蛋白-1（PC 1）和多囊蛋白-2（PC 2）的PKD 1（约85%的病例）或PKD 2（约15%的病例）突变引起。它们的功能受损通常导致细胞内Ca 2+池减少，PC 1-和PC 2-相互作用和效应蛋白改变细胞信号传导，上皮细胞极性丧失和肾细胞生长失调。除了PKD 1和PKD 2基因的突变之外，突变导致初级纤毛的丧失，这诱导了外部机械感觉和可溶性线索的感知缺陷，再次解除了肾细胞生长的调节。最近，已经确定了AURKA、NEDD 9和SRC作为纤毛完整性、PC 2活性、细胞内Ca 2+反应和与ADPKD病理相关的额外信号传导的调节剂的重要作用。在所描述的项目中，将检验以下假设：1）AURKA、NEDD 9和SRC的功能异常在囊肿发生中相互关联且常见，2）针对AURKA和SRC的靶向治疗可能对NEDD 9状态相关的PKD有价值。因此，将分析Nedd 9-/-基因型对Pkd 1和Pkd 2条件性消融小鼠模型中囊肿形成的影响。此外，将在肾细胞系中剖析NEDD 9、AURKA和SRC在与囊肿形成相关的信号传导途径中的相互作用，并最终评价AURKA抑制剂在限制囊肿形成中的作用。该提案的总体目标是更好地了解NEDD 9及其相互作用伙伴AURKA和SRC激酶的相互关联功能，这既是对PKD基础生物学产生基本见解的一种方式，也是提出新的和可获得的治疗策略的目标。