Ocular Inflammatory Mediators in the Pathophysiology of Diabetic Retinopathy

糖尿病视网膜病变病理生理学中的眼部炎症介质

• 批准号: 10480946
• 负责人: Stephen Jae Kim
• 金额: $ 41.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480946
• 关键词: Adrenal Cortex Hormones; Adult; Age; Anti-Inflammatory Agents; Antiinflammatory Effect; Background Diabetic Retinopathy; Bilateral; Biochemical; Biological Markers; Blindness; Blood Glucose; Blood Vessels; Blood capillaries; Cataract; Chronic; Clinical; Cornea; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnostic tests; Dinoprostone; Disease; Disease Progression; Early treatment; Endothelial Cells; Enrollment; Extravasation; Eye; Formulation; Functional disorder; Fundus photography; Future; Glaucoma; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Hypertension; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interleukin-6; Interleukin-8; Ketorolac; Legal Blindness; Leukocytes; Long-Term Effects; Measures; Mediating; Mediator of activation protein; Methods; Natural History; Non-Steroidal Anti-Inflammatory Agents; Optical Coherence Tomography; Oral; Pathogenicity; Pathology; Patients; Penetration; Permeability; Pharmacology; Placebos; Play; Principal Investigator; Randomized; Research; Retina; Retinal Diseases; Risk; Role; Sampling; Self Administration; Serum; Severities; System; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Topical application; Vascular Endothelial Growth Factors; Vascular Permeabilities; Visual impairment; Vitreous humor; Work; aqueous; base; blood glucose regulation; blood pressure control; celecoxib; cytokine; developmental prosopagnosia; diabetic; diabetic patient; disability; disorder risk; experience; innovation; macula; macular edema; new therapeutic target; novel; novel marker; patient stratification; prevent; prognostic; retinal ischemia; risk stratification; screening; treatment response

Project Summary Diabetic retinopathy (DR) is a major cause of blindness worldwide. DR progresses in many patients despite preventable measures such as blood sugar and blood pressure control. Other available treatments require invasive eye injections and are often ineffective—DR remains the leading cause of legal blindness among working-age adults. Current diagnostic tests fail to identify early disease stages or predict disease progression. Consequently, new biomarkers and therapeutic strategies are needed. DR is an established inflammatory disease with leukocyte involvement. Many inflammatory cytokines (products of leukocytes) are consistently elevated in the aqueous and vitreous of patients with advanced DR and diabetic macular edema (DME). Inflammatory mediators are candidates for direct biomarkers that may predict DR progression as well as treatment response. To date the only validated prognostic DR biomarker is the circulating glycemia marker glycated hemoglobin (HbA1C). HbA1C screening, however, reflects glucose control, which indicates disease risk as opposed to DR pathology. Our central hypothesis is that intraocular inflammatory mediators such as PGE2, IL-6, and IL-8 are markers of DR severity and therefore predict risk of disease progression. Equally important, they represent potential novel targets for inhibition. We have recently demonstrated that topically applied ketorolac, a nonsteroidal anti- inflammatory drug, achieves therapeutic vitreous levels and significantly reduces several elevated inflammatory mediators in eyes with DR. These observations and its commercial availability provide rationale to investigate the relationship of inflammatory mediators with DR severity and the long-term effects of chronic topical administration of ketorolac in diabetic patients. Our current goals include confirming inflammation mediators are biomarkers of both systemic diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects localized ocular inflammation, however, is technically easier to collect with less risk. We will also determine the long-term effects of sustained ketorolac application on intraocular cytokine levels, DR progression, and DME incidence. Our proposal is the first to use a cornea-permeable NSAID for the treatment of DR. We believe local inflammation control in the eye will transform future treatment options for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators through all DR stages has the capacity to reduce or prevent disability in millions of patients per year.

项目摘要 糖尿病性视网膜病（DR）是全球失明的主要原因。许多患者的进展 可预防的措施，例如血糖和血压控制。其他可用治疗需要 注射侵入性的注射，常常是无效的 - DR仍然是法律失明的主要原因 成年人。当前的诊断测试无法识别早期疾病阶段或预测疾病进展。 因此，需要新的生物标志物和治疗策略。 DR是一种既定的炎症性疾病，具有白细胞参与。许多炎性细胞因子（产品 白细胞的水性和糖尿病患者的玻璃体持续升高 黄斑水肿（DME）。炎症介质是直接生物标志物的候选者，可以预测DR 进展和治疗反应。迄今为止，唯一经过验证的预后生物标志物是 循环血糖标记糖糖糖糖（HBA1C）。但是，HBA1C筛选反映了葡萄糖 控制，表明疾病风险与DR病理学相反。 我们的中心假设是眼内炎症介质（例如PGE2，IL-6和IL-8）是标记 DR严重程度，因此预测疾病进展的风险。同样重要的是，它们代表潜在的小说 抑制目标。我们最近证明，局部应用Ketorolac，一种非甾体类抗 - 炎症药，达到热玻璃体水平，并显着降低了几种升高 Dr.这些观察及其商业可用性为 调查炎症介质与DR严重程度的关系和慢性的长期影响 糖尿病患者的酮洛洛克局部给药。 我们目前的目标包括确认炎症介质是全身性糖尿病和DR的生物标志物 像玻璃体幽默一样，水都反映了局部的眼注射， 但是，从技术上讲，风险较小。我们还将确定持续的长期影响 酮洛克拉克在眼内细胞因子水平，DR进展和DME入口上的应用。我们的建议是 首先使用可渗透的NSAID来治疗DR。 我们认为，眼睛中的局部炎症控制将改变糖尿病患者的未来治疗选择 面对失明。通过所有DR阶段跟踪和抑制局部炎症介体的能力 每年减少或预防数百万患者的残疾。