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）在世界范围内的发病率为1:400至1:1000，通常表现在中年，受影响的个体进展为终末期肾病。迄今为止，还没有特定的治疗方法被证明可以预防或延迟ADPKD，尽管目前有许多新兴的PKD治疗策略处于临床前或临床试验阶段。ADPKD由编码多囊蛋白-1 （PC1）和多囊蛋白-2 （PC2）的PKD1（约85%的病例）或PKD2（约15%的病例）突变引起。它们的功能受损通常导致细胞内Ca2+池减少，PC1-和pc2相互作用和效应蛋白的细胞信号传导改变，上皮细胞极性丧失，肾细胞生长失调。除了PKD1和PKD2基因的突变外，突变还会导致初级纤毛的缺失，从而导致对外部机械感觉和可溶性信号的感知缺陷，再次导致肾细胞生长失调。最近，AURKA， NEDD9和SRC作为纤毛完整性，PC2活性，细胞内Ca2+反应和与ADPKD病理相关的其他信号的调节因子的重要作用已被确立。在所描述的项目中，我们将验证以下假设：1)AURKA、NEDD9和SRC的异常功能在膀胱发生中是相互关联且常见的；2)针对AURKA和SRC的靶向治疗可能在PKD中有价值，这取决于NEDD9的状态。因此，我们将分析Nedd9-/-基因型对Pkd1和Pkd2条件消融小鼠模型中膀胱发生的影响。我们将进一步研究NEDD9、AURKA和SRC在肾细胞系中与囊形成相关的信号通路中的相互作用，并最终评估AURKA抑制剂在限制囊肿形成中的作用。本提案的总体目标是更好地了解NEDD9及其相互作用伙伴AURKA和SRC激酶的相互作用功能，这既是对PKD基本生物学的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。

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.