Insulin-therapy resistant epigenetic modifications in diabetic retinopathy

描述（由申请人提供）：糖尿病视网膜病变仍然是导致工作年龄成年人失明的主要原因。目前，除了胰岛素替代疗法和血压控制之外，还没有批准和证明的治疗糖尿病视网膜病变的方法。最近的纵向研究报告表明，尽管实现了稳定的血糖水平和HbA1c控制，但以前接受非强化胰岛素治疗的患者发生糖尿病视网膜病变和其他并发症的比例仍然较高。这为代谢记忆假说提供了第一个大规模的临床证据，在代谢记忆假说中，一段时间的不良糖尿病管理持续影响视网膜病变和其他并发症的发展，即使在获得良好控制后的数年内。了解代谢记忆在并发症发展中的作用是非常必要的，因为记忆现象显然没有被目前的治疗方案所克服。这一临床现象也引发了以下问题：血糖控制不良时发生了哪些分子事件？这些事件如何在血糖控制良好后持续数年？本提案试图通过对一种假说的调查来解决这一问题，即控制不良会导致表观基因组的变化，而这种变化不会随着糖尿病管理的改善而完全逆转。在拟议的研究中，我们将定义视网膜基因启动子DNA甲基化和相关的染色质修饰在糖尿病与可变血糖控制的背景下。然后，我们将使用生物信息学工具将表观遗传状态与视网膜基因/蛋白表达进行比较。表观遗传变化将通过正交法证实，由此产生的转录物和蛋白质表达变化将定位于特定的视网膜层和细胞类型。最后，调控DNA甲基化和组蛋白修饰的过程将被检查。这些研究将为未来寻求维持或恢复正常视网膜表观遗传状态的干预性研究以及研究高血糖期间特定基因如何靶向表观遗传修饰的机制研究提供基础。

DESCRIPTION (provided by applicant): Diabetic retinopathy remains the leading cause of blindness in working age adults. Currently, there are no approved and demonstrated treatments for diabetic retinopathy aside from insulin replacement therapy and blood pressure control. Recent longitudinal study reports have demonstrated that despite achieving stable blood glucose levels and HbA1c control, patients formerly under non-intensive insulin therapy continue to have a higher rate of developing diabetic retinopathy, and other complications. This provides the first large-scale clinical evidence for the hypothesis of metabolic memory, in which a period of poor diabetes management continues to impact development of retinopathy and other complications for years after good control has been achieved. Understanding the role of metabolic memory in complication development is vitally needed as the memory phenomenon is obviously not overcome by current treatment regimens. This clinical phenomenon also leads to the questions of what molecular events occur during poor control and how do these events persist for years after good glycemic control is established. This proposal seeks to address this issue through an investigation of the hypothesis that poor control causes epigenomic changes that are not fully reversed with improved diabetes management. In the proposed studies we will define retinal gene promoter DNA methylation and associated chromatin modifications in the context of diabetes with variable glycemic control. We will then use bioinformatics tools to compare the epigenetic state to retinal gene/protein expression. Epigenetic changes will be confirmed by orthogonal methods and the resulting transcript and protein expression changes will be localized to specific retinal layers and cell types. Lastly the processes that regulate DNA methylation and histone modification will be examined. These studies will serve as the basis for future interventional studies which seek to maintain or return the normal retina epigenetic state as well as mechanistic studies investigating how specific genes are targeted for epigenetic modifications during hyperglycemia. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy remains the leading cause of blindness in working age adults and recent clinical studies have demonstrated that despite achieving good diabetes control, patients with previously poor diabetes control continue to have a higher rate of developing diabetic retinopathy and other complications. This study will investigate the potential epigenetic basis of this metabolic memory phenomenon. Understanding the role of epigenetic changes in diabetic retinopathy will open new avenues for development of therapies which seek to maintain or restore the pre-diabetic state.