Uric Acid and Diabetic Retinopathy

尿酸和糖尿病视网膜病变

• 批准号: 9789891
• 负责人: MANUELA BARTOLI
• 金额: $ 38.19万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789891
• 关键词: Adjuvant Therapy; Adult; Allopurinol; Biological Markers; Blindness; Blood Vessels; Blood-Retinal Barrier; Cardiovascular Diseases; Catabolism; Cell Death; Cells; Clinical; Clinical Management; Clinical Research; Complications of Diabetes Mellitus; Crystallization; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Progression; Early Intervention; Endothelial Cells; Epidemic; Epigenetic Process; Epithelial Cells; Event; Experimental Diabetes Mellitus; Exposure to; Functional disorder; Genetic; Glucose; Goals; Homeostasis; Human; Hyperglycemia; Hyperuricemia; Incidence; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; Light; Literature; Long-Term Effects; Macromolecular Complexes; Metabolic; MicroRNAs; Molecular; Monitor; Outcome; Oxidative Stress; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Pilot Projects; Process; Production; Purines; Purinoceptor; Rattus; Receptor Activation; Research Design; Retina; Retinal; Rodent; Role; Safety; Sampling; Serum; Sterility; Streptozocin; Stress; System; Toll-like receptors; Urate; Uric Acid; XDH gene; base; cost; diabetic; diabetic rat; differential expression; experimental study; global health; marenostrin; neurovascular injury; novel; novel diagnostics; novel therapeutics; side effect; tool

Diabetic retinopathy (DR) is a potentially blinding complication of diabetes mellitus and the leading cause of blindness in adults. DR incidence is projected to rise with epidemic proportion causing a serious global health problem. The identification of new therapies as well as new diagnostic tools to allow early intervention are urgently needed. We have designed studies to demonstrate the novel hypothesis that enhanced production and accumulation of monosodium urate (MSU) in retinal cells contributes to DR induction and progression. Rationale for the proposed studies is provided by emerging evidence suggesting that accumulation of MSU contributes to the development of diabetes and its complications. Our preliminary data and evidence provided by the literature confirm this role for MSU in DR. MSU is the crystal form of uric acid (UA), a by-product of the purine catabolism. Increased intracellular production of UA/MSU alters cell homeostasis leading to oxidative stress, inflammation and, potentially, cell death. Our preliminary studies show that UA/MSU formation and accumulation in the diabetic human and rodent retina is significantly increased. Moreover, treatment of diabetic rats with hypouricemic drugs halts retinal inflammation and retinal blood barrier dysfunction. Much of UA/MS pathogenic effects have been attributed to its alarmin-like function in activating the nod-like pyrin 3 (NLRP3)- inflammasome to promote sterile inflammation. Our preliminary data show that UA/MSU exerts a synergistic activity with glucidic stress in promoting NLRP3-inflammasome activation and consequent production of interleukin-1beta (IL-1). In addition, treatment of STZ-rats with hypouricemic drugs down-regulate inflammasome activation and IL-1 production further supporting the hypothesis of UA/MSU pathogenic role in DR. As part of purine metabolic processing, UA/MSU production could be impacted by dysfunction of adenosinergic and purinergic systems. This implies that MSU monitoring and/or modulation could also account/reflect changes in these systems. Based on this evidence we have designed studies to shed light on the molecular basis regulating MSU formation and mode of action in the diabetic retina and in retinal epithelial and endothelial cells, to: Aim 1) Determine the mechanisms of enhanced UA/MSU production and accumulation in the diabetic retina. Aim 2) Determine the mechanism of MSU pro-inflammatory effects in the diabetic retina Aim 3) Determine the long-term effects of hypouricemic drugs on diabetes-induced retinal neurovascular injury.

糖尿病视网膜病变（DR）是糖尿病的潜在致盲并发症，并且是糖尿病视网膜病变的主要原因。 成年人的失明预计DR发病率将随着流行比例的上升而上升，导致严重的全球健康问题 问题.确定新的治疗方法以及新的诊断工具，以允许早期干预， 迫切需要。我们设计了研究来证明新的假设，即提高产量和 在视网膜细胞中，尿酸盐（MSU）的积累有助于DR的诱导和进展。 新出现的证据表明，MSU的积累 有助于糖尿病及其并发症的发展。我们提供的初步数据和证据 通过文献证实了MSU在DR中的这种作用。MSU是尿酸（UA）的晶体形式，尿酸是 嘌呤钙UA/MSU的细胞内产生增加改变了细胞内稳态，导致氧化应激。 压力、炎症和潜在的细胞死亡。我们的初步研究表明，UA/MSU的形成和 在糖尿病患者和啮齿动物视网膜中的累积显著增加。此外，糖尿病的治疗 使用低尿酸血症药物的大鼠停止视网膜炎症和视网膜血液屏障功能障碍。大部分UA/MS 致病作用归因于其在激活类Pyrin 3（NLRP 3）中的alarmin样功能。 炎性小体促进无菌性炎症。我们的初步数据表明，UA/MSU发挥协同作用， 在促进NLRP 3-炎性体活化和随后的 白细胞介素-1 β（IL-1 β）。此外，用降尿酸药物治疗STZ大鼠， 炎性小体激活和IL-1 β产生进一步支持UA/MSU致病作用的假设， 博士作为嘌呤代谢过程的一部分，UA/MSU的产生可能受到嘌呤代谢功能障碍的影响。 腺苷能和嘌呤能系统。这意味着MSU监测和/或调制也可以 说明/反映这些系统中的变化。基于这些证据，我们设计了研究， 调节糖尿病视网膜和视网膜上皮中MSU形成和作用方式的分子基础 目的1）确定UA/MSU产生和积累增加的机制 在糖尿病视网膜中。目的2）探讨MSU在糖尿病视网膜中的促炎作用机制 目的3）观察降尿酸药物对糖尿病视网膜神经血管损伤的远期影响。