Uric Acid and Diabetic Retinopathy

尿酸和糖尿病视网膜病变

• 批准号: 10238862
• 负责人: MANUELA BARTOLI
• 金额: $ 37.35万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238862
• 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; 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)是糖尿病的一种潜在致盲并发症，是糖尿病的主要病因。 成人失明。DR发病率预计将上升，流行比例将导致严重的全球健康 有问题。识别新的治疗方法以及允许早期干预的新诊断工具是 急需之物。我们设计了一些研究来证明这一新的假设，即提高产量和 尿酸单钠(MSU)在视网膜细胞中的积聚有助于DR的诱导和进展。 新出现的证据表明，MSU的积累为拟议的研究提供了理由 导致糖尿病及其并发症的发生。我们提供的初步数据和证据 通过文献证实，MSU博士的这种作用是尿酸(UA)的结晶形式，尿酸是尿酸的副产品 嘌呤分解代谢。细胞内UA/MSU产量增加改变细胞内平衡导致氧化 压力、炎症和潜在的细胞死亡。初步研究表明，UA/MSU的形成和 糖尿病人和啮齿动物视网膜中的蓄积显著增加。此外，糖尿病的治疗 服用低尿酸血症药物的大鼠可以阻止视网膜炎症和视网膜血屏障功能障碍。UA/MS的大部分 致病作用归因于其在激活NLRP3(NLRP3)方面的警报蛋白样功能- 促进无菌炎症的炎性小体。我们的初步数据显示，UA/MSU发挥了协同作用 糖应激促进NLRP3-炎症体激活及其产物的活性 白介素1β(IL-1)。此外，低尿酸血症药物对STZ-大鼠的治疗也有下调作用 炎症小体激活和IL-1的产生进一步支持了UA/MSU致病作用的假说 作为嘌呤代谢过程的一部分，UA/MSU的产生可能会受到以下因素的影响 腺苷能和嘌呤能系统。这意味着MSU监控和/或调制还可以 说明/反映这些系统中的更改。基于这一证据，我们设计了一些研究，以阐明 调控MSU形成的分子基础及其在糖尿病视网膜和视网膜上皮中的作用方式 和内皮细胞，以：目的1)确定增加UA/MSU产生和积累的机制 在糖尿病视网膜中。目的2)探讨MSU在糖尿病视网膜的促炎作用机制 目的3)观察低尿酸血症药物对糖尿病视网膜神经血管损伤的远期疗效。