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工作年龄成人失明的主要原因。目前，除了胰岛素替代疗法和血压控制外，还没有批准和证明的糖尿病视网膜病变治疗方法。最近的纵向研究报告表明，尽管达到了稳定的血糖水平和HbA 1c控制，以前接受非强化胰岛素治疗的患者仍然有较高的糖尿病视网膜病变和其他并发症发生率。这为代谢记忆的假设提供了第一个大规模的临床证据，其中一段时间的不良糖尿病管理继续影响视网膜病变和其他并发症的发展，在良好的控制之后多年。了解代谢记忆在并发症发展中的作用是非常必要的，因为记忆现象显然不能被目前的治疗方案所克服。这种临床现象也导致了这样的问题，即在血糖控制不良期间发生了哪些分子事件，以及在建立良好的血糖控制后，这些事件如何持续多年。该提案旨在通过调查以下假设来解决这一问题，即控制不良导致表观基因组变化，这些变化不能通过改善糖尿病管理而完全逆转。在本研究中，我们将在血糖控制不稳定的糖尿病患者中确定视网膜基因启动子DNA甲基化和相关的染色质修饰。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/蛋白质表达进行比较。表观遗传变化将通过正交方法确认，并且所得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，调节DNA甲基化和组蛋白修饰的过程将被检查。这些研究将作为未来干预性研究的基础，这些研究旨在维持或恢复正常的视网膜表观遗传状态，以及研究在高血糖期间如何靶向特定基因进行表观遗传修饰的机制研究。 公共卫生相关性：糖尿病视网膜病变仍然是工作年龄成年人失明的主要原因，最近的临床研究表明，尽管糖尿病控制良好，但先前糖尿病控制不佳的患者仍然有较高的糖尿病视网膜病变和其他并发症发生率。本研究将探讨这种代谢记忆现象的潜在表观遗传基础。了解表观遗传变化在糖尿病视网膜病变中的作用，将为寻求维持或恢复糖尿病前期状态的疗法的开发开辟新的途径。

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.