Identification of Immunomodulators for Diabetic Retinopathy Therapeutics

糖尿病视网膜病变治疗的免疫调节剂的鉴定

• 批准号: 10132337
• 负责人: Patricia R Taylor
• 金额: $ 39.04万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10132337
• 关键词: Address; Autoimmune; Autoimmune Diseases; Background Diabetic Retinopathy; Binding; Biological Assay; Blindness; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Cell Death; Cells; Chronic; Complications of Diabetes Mellitus; Cytokine Receptors; Data; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diagnosis; Endothelial Cells; Epidemic; Event; Extravasation; Gene Silencing; Goals; Health; Human; Immunoblot Analysis; Immunomodulators; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin Receptor; Interleukin-17; Interleukins; Lasers; Lead; Lesion; Leukocytes; Link; MAPK7 gene; Mediating; Modeling; Muller' s cell; Mus; Neuroglia; Oxidative Stress; Pathogenesis; Pathologic; Pharmacology; Phosphotransferases; Photoreceptors; Play; Population; Prediabetes syndrome; Preventive therapy; Procedures; Production; Proteins; Reactive Oxygen Species; Reporting; Research Project Grants; Retina; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Signaling Protein; Steroids; Streptozocin; Stress; Subcutaneous Injections; TNF Receptor-Associated Factors; TRAF4 gene; TRAF6 gene; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Transgenic Mice; Treatment Cost; Type 2 diabetic; United States; Vascular Permeabilities; Vegf Inhibitor; Vision Disorders; Western World; aging population; clinically relevant; cytokine; diabetic; early onset; efficacy evaluation; humanized monoclonal antibodies; immunoregulation; in vivo; inhibitor/antagonist; mouse model; new therapeutic target; novel therapeutics; proliferative diabetic retinopathy; receptor; receptor expression; small molecule inhibitor; therapeutic target; trait; type I diabetic

ABSTRACT More than 9% of the US population has diabetes, with an additional 25% being treated for pre-diabetes, and this epidemic continues to rise annually. As diabetes progresses, >60% of Type II and >95% of Type I diabetics develop diabetic retinopathy; one of the leading causes of blindness in the working-age population worldwide. Currently, there are no preventative therapies to inhibit the asymptomatic chronic inflammation that slowly destroys retinal cells, which leads to vascular lesions and the onset of diabetic retinopathy. With such a significant impact on human health, new therapies are required to stay abreast of this diabetes complication. One of the most promising therapeutic targets lie within the inflammatory response, because inflammation can mediate much of the pathogenesis in diabetes complications. In a murine model of Streptozotocin (STZ)- induced-diabetes, we determined that diabetes mediated the production of Interleukin-17A (IL-17), one of the most prevalent cytokines associated with autoimmune and inflammatory pathogenesis. We also found that IL- 17 induced vascular permeability and capillary degeneration in the retina, which are hallmarks of non- proliferative diabetic retinopathy. Finally, we identified IL-17 receptor and the CIKS (Connection to IB Kinase and Stress activated protein) adaptor molecule constitutively expressed on multiple retina cells, which elicits retinal inflammation, oxidative stress, and the vascular lesions. The goal of this proposal is to unravel the IL-17 receptor/CIKS signaling events involved in retinal pathogenesis to reveal novel therapeutic targets for the early onset of diabetic retinopathy. We postulate that diabetes mediates a cascade of CIKS-TRAF (TNF Receptor Associated Factor) signaling events that initiate oxidative stress and retinal inflammation, which lead to vascular permeability and capillary degeneration in the retina. This is a precursor to the onset of proliferative diabetic retinopathy and vision loss. By using murine models of STZ-induced diabetes and ex vivo retina assays, we will identify the mechanism within the CIKS-TRAF signaling cascade that initiates retinal inflammation and pathogenesis. Through these studies therapeutic targets will be identified, which we postulate will delay the onset of diabetic retinopathy and inhibit vision loss.

摘要 超过9%的美国人口患有糖尿病，另有25%的人正在接受糖尿病前期治疗， 这一流行病继续逐年上升。随着糖尿病的进展，>60%的II型和>95%的I型糖尿病患者 糖尿病患者患糖尿病性视网膜病变;这是工作年龄人群失明的主要原因之一 国际吧目前，没有预防性疗法来抑制无症状的慢性炎症， 缓慢破坏视网膜细胞，导致血管病变和糖尿病视网膜病变的发生。有了这样的 尽管糖尿病对人类健康有重大影响，但需要新的治疗方法来跟上这种糖尿病并发症。 最有希望的治疗靶点之一在于炎症反应，因为炎症可以 介导糖尿病并发症的发病机制。在链脲佐菌素（STZ）的鼠模型中， 诱导糖尿病，我们确定糖尿病介导白细胞介素-17A（IL-17）的产生， 与自身免疫和炎症发病机制相关的最普遍的细胞因子。我们还发现IL- 17诱导视网膜中的血管通透性和毛细血管变性，这是非- 增殖性糖尿病视网膜病变最后，我们鉴定了IL-17受体和CIKS（Connection to IL-17 B Kinase 和应激激活蛋白）衔接分子组成型表达在多个视网膜细胞上， 视网膜炎症、氧化应激和血管病变。这项提案的目标是解开IL-17 受体/CIKS信号转导事件参与视网膜发病机制，以揭示早期治疗的新靶点。 糖尿病视网膜病变的发病。我们推测糖尿病介导CIKS-TRAF（TNF受体）级联反应， 相关因子）信号传导事件，引发氧化应激和视网膜炎症，导致 视网膜中的血管渗透性和毛细血管变性。这是一个前兆的发病增殖 糖尿病视网膜病变和视力丧失。通过使用STZ诱导的糖尿病和离体视网膜的小鼠模型， 我们将确定CIKS-TRAF信号级联中启动视网膜神经元凋亡的机制。 炎症和发病机制。通过这些研究，将确定治疗靶点， 假设将推迟糖尿病视网膜病变的发病并抑制视力丧失。