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.

糖尿病视网膜病变仍然是工作年龄成年人视力丧失的主要原因。以前的研究 已经导致抗VEGF疗法的发展，其是增殖性肿瘤的有效治疗。 糖尿病视网膜病变和黄斑水肿，而其他患者则无反应。为 非增殖性糖尿病视网膜病变的治疗，除了良好的血糖控制外，几乎没有可用的选择， 这对许多患者来说是有问题的。最近的发现提供了新的见解， 糖尿病视网膜病变的潜在机制，并表明，除了氧化应激，增加 炎症可能是糖尿病诱导的视网膜损伤的主要致病因素。我们最近报道 高葡萄糖显著增加高迁移率族蛋白B1（HMGB 1）蛋白水平，表明 alarmin系统在调节视网膜对高糖反应中的潜在作用。hmgb 1是 广泛参与炎症;它可以作为伴侣蛋白调节细胞核中的转录， 由免疫细胞分泌，与p53相互作用，并激活细胞因子释放。因此，它提供了一个 有希望的目标，以减弱视网膜中的炎症反应。由于其多种机制， 激活和各种细胞类型中的作用，提高对HMGB 1细胞调节的理解 视网膜中的活动变得越来越重要。我们的初步数据表明， 生长因子结合蛋白3（IGFBP-3）可抑制高糖诱导的HMGB 1水平升高 视网膜内皮细胞（REC）。我们以前曾报道IGFBP-3基因敲除小鼠视网膜病变， 损害类似于糖尿病视网膜病变的啮齿动物模型，尽管正常的葡萄糖水平。除了 IGFBP-3，研究表明PKA可以直接磷酸化酵母HMGB 1的Box A区域 导致HMGB 1作用减少。研究还表明，SIRT 1的增加促进了去乙酰化 HMGB 1，导致细胞质易位减少。因此，有科学的理由进行调查， PKA、Epac 1、IGFBP-3和SIRT 1对HMGB 1的调节。此外，抑制HMGB 1 使用抑制剂（Escherichin）的活性恢复视网膜厚度并减少视网膜变性 在小鼠视网膜缺血/再灌注损伤的体内模型中，这些数据导致了 假设视网膜中HMGB 1活性的抑制可以保护糖尿病诱导的损伤。我们 总体目标是确定PKA和Epac 1通路抑制 HMGB 1/炎症诱导的视网膜损伤并作为可能阻断糖尿病性视网膜病变的保护性途径 视网膜损伤