内质网应激参与糖尿病肾病足细胞损伤。Wnt/β-catenin通路调节内质网应激，但其在糖尿病肾病足细胞内质网应激与表观遗传调控中的作用尚不清楚。申请者前期研究表明：LINC00355长链非编码RNA在糖尿病肾病患者肾组织上调促进足细胞内质网应激并恶化肾功能；LINC00355定位于足细胞胞核并特异结合EZH1，增加β-catenin抑制子CTNNBIP1启动子H3K4三甲基化抑制其表达，从而激活β-catenin通路活化内质网应激。为此，我们提出LINC00355招募EZH1增加CTNNBIP1启动子H3K4三甲基化通过表观遗传调控内质网应激和糖尿病足细胞损伤的科学假说。为验证假说，我们拟应用糖尿病肾病患者肾组织并通过体内外实验和转基因动物，深入研究LINC00355/EZH1/CTNNBIP1的表观遗传调控网络，阐明LINC00355在糖尿病肾病中的作用，明确其生物学功能及调控机制。

Endoplasmic reticulum stress (ER stress) is involved in podocyte injury in diabetic nephropathy. Wnt/β-catenin signaling modulates ER stress, yet the epigenetic regulation of β-catenin in ER stress and podocyte injury is still unclear. Our preliminary data have shown that upregulation of long noncoding RNA LINC00355 in DN triggers ER stress and worsens renal function. LINC00355 is localized in the nucleus and exerts biological functions by directly binding EZH1, which epigenetically targets CTNNBIP1, the inhibitor of Wnt/β-catenin, through repressive trimethylation of H3K4 and activates Wnt/β-catenin signaling and ER stress. Based on the preliminary results, we propose that LINC00355 recruits EZH1 to the promoter region of CTNNBIP1 and trimethylates H3K4 to regulate ER-stress induced podocyte injury in DN. By using renal biopsy samples from DN patients as well as in vitro and in vivo assays and LINC00355 transgenic mice, we will interrogate the regulated epigenetic network of LINC00355/EZH1/CTNNBIP1. The function of LINC00355 will be investigated and biological regulatory mechanisms will be elucidated in DN.