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

基本信息

批准号：
10249084
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
项目类别：
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/10249084
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 regulation 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

项目摘要

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.

项目概要糖尿病视网膜病变 (DR) 是全世界许多患者失明的主要原因。其他可用的治疗方法需要采取其他可预防的措施，例如控制血糖和血压。侵入性眼部注射，且常常无效——DR 仍然是导致法定失明的主要原因目前的诊断测试无法识别早期疾病阶段或预测疾病进展。经过测试，需要新的生物标志物和治疗策略。 DR 是一种与白细胞相关的炎症性疾病。晚期 DR 和糖尿病患者的房水和玻璃体中的白细胞）持续升高黄斑水肿 (DME) 是可预测 DR 的直接生物标志物的候选者。迄今为止，唯一经过验证的预后 DR 生物标志物是然而，循环血糖标记物糖化血红蛋白 (HbA1C) 筛查反映了葡萄糖。控制，这表明疾病风险而不是 DR 病理学。我们的中心假设是眼内炎症介质如 PGE2、IL-6 和 IL-8 是眼内炎症的标志物。 DR 严重程度并因此预测疾病进展的风险同样重要，它们代表了潜在的新颖性。我们最近证明了局部应用酮咯酸，一种非甾体抗-抑制药物。炎症药物，达到治疗玻璃体水平并显着降低一些升高的这些观察结果及其商业可用性为 DR 眼中的炎症介质提供了理论基础。研究炎症介质与 DR 严重程度的关系以及慢性炎症的长期影响糖尿病患者局部给予酮咯酸。我们当前的目标包括确认炎症介质是系统性糖尿病和 DR 的生物标志物与玻璃体液一样，房水反映了局部眼部炎症，然而，从技术上讲，收集起来更容易，风险也更小，我们还将确定持续的长期影响。酮咯酸对眼内细胞因子水平、DR 进展和 DME 发生率的影响。首先使用角膜渗透性 NSAID 来治疗 DR。我们相信眼部局部炎症控制将改变糖尿病患者未来的治疗选择面对失明，有能力在所有 DR 阶段跟踪和抑制局部炎症介质。每年减少或预防数百万患者的残疾。