环状RNA-cZNF532介导的周细胞与内皮细胞crosstalk在糖尿病视网膜血管病变中的作用及机制研究

Diabetic retinopathy (DR) is still the major ocular disease that leads to blindness. Retinal microvascular dysfunction is recognized as the major cause of vision loss. Retinal microvasculature is mainly composed of endothelial cells and pericytes. Previous studies mainly focused on the role of endothelial cell, but ignored endothelial cell-pericyte crosstalk in diabetes mellitus-induced microvascular dysfunction. Circular RNAs are a class of stable and conserved non-coding RNA molecules, and plays important roles in several physiological and pathological processes. Our previous study has revealed that cZNF532 is expressed in pericytes and endothelial cells. Its expression is significantly up-regulated in high glucose-treated cells and diabetic retinas. In this study, we will determine cZNF532 expression pattern in the endothelial cell/pericyte or retina upon high glucose stress at different time points, clarify the role of cZNF532 in endothelial-pericyte crosstalk and retinal microvascular dysfunction through in vitro or in vivo intervention of cZNF532 expression, and reveal the molecular mechanism of cZNF532-mediated retinal microvascular dysfunction. This study will provide a novel insight into the prevention and treatment of diabetes mellitus-induced microvascular dysfunction.

糖尿病视网膜病变是主要的致盲性眼病，视网膜血管病变被认为是致盲的主要病因。视网膜血管主要由内皮细胞和周细胞构成，既往研究大多关注血管内皮功能异常，忽视了周细胞与内皮细胞crosstalk对血管病变的影响。环状RNA（circRNAs）是一类稳定和保守表达的非编码RNA分子，调控众多生理和病理过程。预实验发现，cZNF532在周细胞和内皮细胞中表达，在高糖损伤的细胞模型和糖尿病动物的视网膜中表达上调。项目拟建立周细胞/内皮细胞的高糖损伤模型和糖尿病动物模型，分析多个压力/时间点的cZNF532表达规律；基于cZNF532表达干预，从细胞和动物水平明确cZNF532在周细胞-内皮细胞的crosstalk和微血管病变中的调控作用；基于生物信息学和分子生物学技术，阐明cZNF532调控微血管病变的分子机制。研究成果有望为防治糖尿病微血管病变提供新思路。

糖尿病视网膜病变是工作人群中排名首位的致盲性眼病，视网膜血管病变被认为是致盲的主要病因。视网膜血管主要由内皮细胞和周细胞构成，既往研究大多关注血管内皮异常，忽视了周细胞对视网膜血管病变的影响。环状RNA（circRNAs）是一类稳定和保守表达的非编码RNA分子，调控众多生理和病理过程。本研究研究了cZNF532在视网膜周细胞病变和血管病变中的调控作用及其调控机制。研究结果发现，cZNF532在周细胞的高糖损伤模型、糖尿病小鼠视网膜和糖网病人的玻璃体中表达上调；cZNF532沉默抑制周细胞增殖、迁移和分化以及向内皮细胞的募集；cZNF532作为miR-29a-3p海绵，调控NG2, LOXL2, and CDK2的表达进而影响周细胞功能；cZNF532沉默或者上调miR-29a-3p加重糖尿病引起的视网膜血管病变。相反，cZNF532过表达或者下调miR-29a-3p表达可以保护糖尿病引起的视网膜周细胞损伤和抑制血管病变的发生。因此，干预cZNF532或者miR-29a-3p的表达有望成为治疗DR疾病的新策略。