Shh信号通路抑制剂治疗ADPKD的机制与靶点的确认研究

ADPKD is one of the most common monogenic diseases in the kidneys and is characterized by numerous fluid-filled renal cysts. ADPKD is caused by mutations in either PKD1 or PKD2, each of which respectively encodes the proteins, polycystin-1 (PC1) and polycystin-2 (PC2). Recent studies indicate that PC1 and PC2 form a protein complex through interaction between their COOH-terminals and associate with the primary cilia of renal epithelial cells. Our recent studies indiate that loss of either polycystins lead to aberrant ciliary formation in renal epithelial cells which may eventually cause renal cyst formation. Sonic Hegdehog (Shh) have been widely reported to be cilioprotein whose dysfunction in mice can result in severe cyclopia and holoprosencephaly as well as a spectrum of other developmental defects, including embryonic lethality, axial pattering abnormality, and loss of distal limb structures.By our preliminary study, we have discovered the molecular links between Shh and PC1/2. We have therefore begun to employ a panel of Shh inhibitors to identify if Shh signaling can serve as theraputic targets in treatment of ADPKD. This proposed study will center on seeking potential therapeutic avenues for human ADPKD.The resulting discoveries will certainly lay theoretical foundation for identifying Shh inhibitors as new therapeutic targets toward ADPKD treatment.

常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease,ADPKD）是一组常见的人类遗传性肾脏疾病。我国约有150 万患者。约有5%的终末肾衰竭由ADPKD所导致。目前为止，临床上尚无公认的ADPKD 的低毒高效的治疗药物。多囊肾疾病目前被认为是与上皮细胞纤毛相关的疾病（ciliopathies）之一。我们研究组的最新报道表明ADPKD致病基因PKD1和PKD2的基因产物polycystin-1（PC1）及-2（PC2）的缺失将导致上皮细胞纤毛结构和功能出现异常。这一发现提示Shh传导通路很可能参与ADPKD的发病机制。因此，本研究将应用我们业已建立的ADPKD和Shh突变小鼠模型以及小分子Shh信号传导通路抑制剂，以确证Shh信号传导通路在ADPKD发病机制中的作用，并为发现Shh抑制剂作为新型治疗ADPKD的药物奠定理论基础

常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease,ADPKD）是一组常见的人类遗传性肾脏疾病。我国约有150 万患者。约有5%的终末.肾衰竭由ADPKD 所导致。目前为止，临床上尚无公认的ADPKD 的低毒高效的治疗药物。多囊肾疾病目前被认为是与上皮细胞纤毛相关的疾病（ciliopathies）之一。我们研究组的最新报道表明ADPKD 致病基因PKD1 和PKD2 的基因产物polycystin-1（PC1）及-2（PC2）的缺失将导致上皮细胞纤毛结构和功能出现异常。这一发现提示Shh 传导通路很可能参与ADPKD 的发病机制。因此，本项目应用我们业已建立的ADPKD 和Shh 突变小鼠模型以及小分子Shh信号传导通路抑制剂，确证Shh 信号传导通路在ADPKD 发病机制中的作用和Shh 抑制剂在该疾病的治疗作用，进而开发出新的治疗药物。

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