miR-340-5p调控组蛋白去甲基化酶JMJD2A在糖尿病视网膜病变代谢记忆分子机制中的作用

Diabetic retinopathy (DR) is the first cause of blindness in the working age population. The "metabolic memory" effect of hyperglycemia in DR patients with poor glycemic control makes the disease continue to progress despite improved glucose control, which is the key factor affecting the effect of DR treatment. Recent studies suggested that epigenetic regulation of miRNA and histone modifications play an important role in the metabolic memory, but the specific mechanism is not clear. Our previous studies found that high glucose treatment decreased miR-340-5p expression in retinal endothelial cells (HRECs), which upregulated the target gene JMJD2A. While JMJD2A may lead to the activation of the inflammatory pathway by mediating histone methylation, and thus promote the metabolic memory effect in HRECs. To test this hypothesis, the research group plan to detect the expression of miR-340-5p, JMJD2A and related inflammatory factor, as well as the relative genome methylation changes, and bidirectionally regulate miR-340-5p levels by transfection technology to verify its role in the metabolic memory, on the basis of the established cellular and animal research system and from the molecular, cellular and tissue levels. The research will provide new indicators and research ideas for understanding the regulation mechanism of hyperglycemia metabolic memory in DR, and a new idea for the prevention and treatment of DR.

糖尿病视网膜病变（DR）为工作年龄段人群首位致盲原因。高血糖的代谢记忆效应使得血糖控制不佳的DR 患者在血糖控制良好后病变继续进展，是影响DR 治疗效果的关键因素，新近研究表明miRNA及组蛋白修饰相关的表观遗传调控在代谢记忆中发挥重要作用，但具体机制尚不明确。我们前期研究发现：高糖处理可下调视网膜内皮细胞miR-340-5p 的表达，其靶基因组蛋白去甲基化酶JMJD2A因而表达上调；而后者可能通过介导组蛋白去甲基化作用导致炎症通路持续激活，进而促发代谢记忆效应。为此，本课题组将在已建立的高血糖代谢记忆细胞和动物模型的基础上，系统动态地检测miR-340-5p、JMJD2A和相关炎症因子的表达，以及相应基因组蛋白甲基化修饰的变化；并通过转染技术双向调节miR-340-5p水平，从而验证其在高糖代谢记忆中的作用及具体机制，为靶向纠正高血糖代谢记忆提供理论依据，为DR 的防治提供新思路。

糖尿病视网膜病变（DR）为工作年龄段人群首位致盲原因。高血糖的代谢记忆效应使得血糖控制不佳的DR 患者在血糖控制良好后病变继续进展，是影响DR 治疗效果的关键因素，新近研究表明miRNA及组蛋白修饰相关的表观遗传调控在代谢记忆中发挥重要作用，但具体机制尚不明确。我们前期研究发现：高糖处理可下调视网膜内皮细胞miR-340-5p 的表达，其靶基因组蛋白去甲基化酶JMJD2A因而表达上调；而后者可能通过介导组蛋白去甲基化作用导致炎症通路持续激活，进而促发代谢记忆效应。为此，本项目瞄准当前本领域科学前沿，利用高血糖代谢记忆细胞和动物模型，系统动态地检测miR-340-5p、JMJD2A和相关炎症因子的表达，以及相应基因组蛋白甲基化修饰的变化；并通过转染技术双向调节miR-340-5p水平，从而阐明了miR-340-5p通过抑制JMJD2A的表达，从而影响相关炎症因子启动子区域H3K9me的甲基化水平，进而调控炎症因子表达的分子机制，为DR干预提供新的靶点，并为寻找DR的早期防治方法提供理论和实验依据。