Inhibition of HMGB1 as a protective mechanism against diabetic retinopathy

抑制 HMGB1 作为糖尿病视网膜病变的保护机制

• 批准号: 9899993
• 负责人: Jena J Steinle
• 金额: $ 44.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899993
• 关键词: Adenylate Cyclase; Adult; Age; Background Diabetic Retinopathy; Blindness; Blood Vessels; Blood capillaries; Cell Nucleus; Cells; Cre-LoxP; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; Data; Deacetylation; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Endothelial Cells; Genetic Transcription; Glucose; Glycyrrhizic Acid; Goals; HMGB1 Protein; Immune; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Insulin-Like Growth Factor Binding Protein 3; Knockout Mice; Modeling; Molecular; Molecular Chaperones; Mus; Neurons; Oxidative Stress; Pathway interactions; Patients; Proteins; Regulation; Regulatory Pathway; Reperfusion Injury; Reporting; Research; Retina; Rodent; Rodent Model; Role; SIRT1 gene; System; TLR4 gene; TNF gene; TP53 gene; Testing; Thick; Work; Yeasts; bevacizumab; cell growth regulation; cell type; cytokine; diabetic; effective therapy; glycemic control; improved; in vivo Model; inhibitor/antagonist; insight; macular edema; proliferative diabetic retinopathy; response; retinal damage; retinal ischemia; targeted treatment; therapeutic target

Diabetic retinopathy remains the leading cause of vision loss in working age adults. Previous research has led to the development of anti-VEGF therapy, which is an effective treatment for proliferative diabetic retinopathy and macular edema in some patients, while other patients are unresponsive. For treatment of non-proliferative diabetic retinopathy, few options are available save good glycemic control, which is problematic for many patients. Recent discoveries offer new insights into the molecular mechanisms underlying diabetic retinopathy and suggest that in addition to oxidative stress, increased inflammation may be a major causative factor in diabetes-induced retinal damage. We recently reported that high glucose significantly increased high mobility group box 1 (HMGB1) protein levels, suggesting a potential role for the alarmin system in regulating retinal responses to high glucose. HMGB1 is extensively involved in inflammation; it can serve as a chaperone to regulate transcription in the nucleus, is secreted by immune cells, interacts with p53, and activates cytokine release. As such, it provides a promising target to blunt the inflammatory response in the retina. Due to its multiple mechanisms of activation and roles in various cell types, an improved understanding of the cellular regulation of HMGB1 actions in the retina becomes increasingly important. Our preliminary data demonstrate that insulin-like growth factor binding protein 3 (IGFBP-3) can inhibit high glucose-induced increases in HMGB1 levels in retinal endothelial cells (REC). We have previously reported that IGFBP-3 KO mice have retinal damage similar to rodent models of diabetic retinopathy, despite normal glucose levels. In addition to IGFBP-3, studies have shown that PKA can directly phosphorylate the Box A region of yeast HMGB1 leading to decreased HMGB1 actions. Studies also showed that increased SIRT1 promoted deacetylation of HMGB1, leading to reduced cytoplasmic translocation. Thus, there is scientific rationale to investigate the regulation of HMGB1 by PKA, Epac1, IGFBP-3, and SIRT1. Furthermore, inhibition of HMGB1 activity using an inhibitor (glycyrrhizin) restored retinal thickness and reduced retinal degenerate capillaries in an in vivo model of retinal ischemia/reperfusion injury in mice. These data have led to the hypothesis that inhibition of HMGB1 activity in the retina protects against diabetes-induced damage. Our overall goal is to determine the mechanisms by which the PKA and Epac1 pathways inhibit HMGB1/inflammation-induced retinal injury and serve as protective pathways that may block diabetic retinal damage.

糖尿病性视网膜病仍然是成年成年人视力丧失的主要原因。先前的研究 导致抗VEGF疗法的发展，这是一种有效的增生治疗 一些患者的糖尿病性视网膜病和黄斑水肿，而其他患者则无反应。为了 治疗非增殖性糖尿病性视网膜病，几乎没有选择可节省良好的血糖控制， 这对许多患者来说是有问题的。最近的发现为分子提供了新的见解 糖尿病性视网膜病的机制，表明除了氧化应激外，还增加了 炎症可能是糖尿病引起的视网膜损伤的主要病因。我们最近报道 高葡萄糖显着增加了高迁移率组框1（HMGB1）蛋白水平，表明A 警报系统在调节对高葡萄糖的视网膜反应中的潜在作用。 HMGB1是 广泛参与炎症；它可以用作调节核中转录的伴侣， 由免疫细胞分泌，与p53相互作用，并激活细胞因子释放。因此，它提供了 有望在视网膜中钝化炎症反应的目标。由于其多种机制 激活和在各种细胞类型中的作用，对HMGB1的细胞调节有了改进的了解 视网膜中的行动变得越来越重要。我们的初步数据表明，胰岛素样 生长因子结合蛋白3（IGFBP-3）可以抑制高葡萄糖诱导的HMGB1水平增加 在视网膜内皮细胞中（REC）。我们以前已经报道IGFBP-3 KO小鼠具有视网膜 尽管葡萄糖水平正常，但类似于糖尿病性视网膜病的啮齿动物模型的损害。此外 IGFBP-3，研究表明，PKA可以直接磷酸化酵母HMGB1的区域 导致HMGB1动作减少。研究还表明，增加的SIRT1促进了脱乙酰基化 HMGB1，导致细胞质易位减少。因此，有科学的理由进行调查 PKA，EPAC1，IGFBP-3和SIRT1对HMGB1的调节。此外，抑制HMGB1 使用抑制剂（甘油林）恢复视网膜厚度并减少视网膜变性的活性 小鼠视网膜缺血/再灌注损伤体内模型中的毛细血管。这些数据导致了 假设视网膜中HMGB1活性的抑制可以预防糖尿病诱导的损害。我们的 总体目标是确定PKA和EPAC1途径的机制 HMGB1/炎症引起的视网膜损伤，并用作可能阻止糖尿病的保护途径 视网膜损害。