Regulation of ciliogenesis and ciliary disassembly by nephrocystins

肾病是一种常染色体隐性遗传的囊性肾病，由肾胱氨酸突变引起。初步结果显示，三种肾囊蛋白（NPHP 1，2，4）调节Hef 1/Aurora A的活性，Hef 1/Aurora A是一种通过激活组蛋白脱乙酰酶（HDAC）触发纤毛解体的复合物。由于HDAC抑制剂挽救了由NPHP 2/Inversin缺失诱导的纤毛发生缺陷，这些发现表明一些肾胱氨酸控制纤毛组装和拆卸之间的平衡。因此，本项目将集中于肾胱氨酸在纤毛发生和纤毛拆卸的调节中的作用。具体目标将1）阐明肾囊蛋白调节纤毛发生和纤毛分解的机制，2）测试哪些纤毛缺陷对HDACi敏感，以及3）建立体外模型以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.