结缔组织生长因子（CTGF）在糖尿病肾病（DKD）发展进程中具有关键性作用，已成为DKD治疗的新靶点。项目组前期研究发现来源于海洋的新吲哚咔唑类化合物HDZ-580具有显著的体内外抗DKD作用，且与CTGF在生物传感芯片上存在特异的相互结合作用，是一种新型CTGF小分子抑制剂。在此基础上，项目组拟采用基因克隆结合分子对接、生物传感芯片等多种集成技术手段，揭示HDZ-580结合CTGF的具体位点和反应模式；采用蛋白印迹、ELISA等多种细胞分子生物学方法研究HDZ-580对CTGF介导DKD生物学功能的影响和HDZ-580拮抗CTGF介导的TGF-β/Smads、Raf/MEK/ERK和p38MAPK信号转导通路；以期系统阐明HDZ-580抗DKD的作用机制。本项目的成功实施不仅为新一类结构骨架的抗DKD药物研发提供分子模板和理论参考，还将为靶向CTGF的抗DKD治疗提供借鉴。

Connective tissue growth factor (CTGF) plays a key role in the process of diabetic kidney disease (DKD), and is a new therapeutic target for DKD. Our preliminary studies indicated that the novel indolocarbazole compound HDZ-580, derived from marine Actinomadura sp.007, had significant anti-DKD effects in vitro and in vivo, and it also had special binding interactions with CTGF by SPR biosensor analysis, indicating a new small molecular inhibitor for CTGF. On that basis, the project intends to identify the binding sites and binding modes by using gene clone combined with molecular docking, SPR and several means of fluorescence spectroscopy and circular dichroism; To explore the effects of HDZ-580 on CTGF induced extracelluar matrix (ECM) accumulation and epithelial-mensenchymal transition (EMT), and furthur in to investigate the inhibitory mechinsms of HDZ-580 on CTGF stimulated TGF-β/Smads, Raf/MEK/ERK and p38MAPK signaling pathways in HBZY-1 and HK-2 cell models by flow cytometry, ELISA, confocal microscope and western blot technology, and eventually fully clarify the anti-DKD mechanisms of HDZ- 580. In summary, the project will not only provide the theoretical reference for the development of novel anti-DKD drugs, but also provide a reference for the anti-DKD therapy targeting to CTGF binding and inhibition.