Regulation of ciliogenesis and ciliary disassembly by nephrocystins

肾病是由肾囊素突变引起的常染色体隐性囊性肾病。初步结果显示，三种肾囊素（NPHP1, 2,4）调节Hef1/Aurora A的活性，Hef1/Aurora A是一种通过激活组蛋白脱羧酶（HDACs）触发纤毛分解的复合物。由于HDAC抑制剂可以挽救因NPHP2/逆转录酶缺失而导致的纤毛发育缺陷，这些研究结果表明，一些肾囊素控制了纤毛组装和拆卸之间的平衡。因此，本项目将侧重于肾囊素在纤毛发生和纤毛脱落调节中的作用。具体目的是：1)阐明肾囊素调节纤毛发生和纤毛脱落的机制；2)检测哪些纤毛缺陷对HDACi敏感；3)建立体外模型筛选促进纤毛发生的化合物，并利用HDACi抑制多囊肾病动物模型中囊肿形成的潜力。

Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations of nephrocystins. Preliminary results revealed that three nephrocystins (NPHP1, 2, 4) regulate the activity of Hef1/Aurora A, a complex that triggers ciliary disassembly through activation of histone deacytelases (HDACs). Since HDAC inhibitors rescue the ciliogenesis defect induced by the loss of NPHP2/lnversin, these findings suggest that some nephrocystins control the balance between ciliary assembly and disassembly. This project will therefore focus on the role of nephrocystins in the regulation of ciliogenesis and ciliary disassembly. The specific aims will 1) elucidate the mechanisms through which nephrocystins regulate ciliogenesis and ciliary disassembly, 2) test which ciliary defects are sensitive to HDACi, and 3) establish an in vitro model to screen for compounds that facilitate ciliogenesis, and exploit the potential of HDACi to suppress cyst formation in animal models of polycystic kidney disease.