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: 10382423
• 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/10382423
• 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; Persons; 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; 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.

抽象的 超过9％的美国人口患有糖尿病，另外25％的人接受了糖尿病前期的治疗，并且 这种流行病每年继续上升。随着糖尿病的进展，II型的60％> I型的95％ 糖尿病患者患糖尿病性视网膜病；劳动年龄人口失明的主要原因之一 全世界。目前，没有预防性疗法可以抑制不对称的慢性感染 慢慢破坏视网膜细胞，导致血管病变和糖尿病性视网膜病的发作。这样的 对人类健康的重大影响，需要新的疗法才能与这种糖尿病并发症保持同步。 炎症反应中最有希望的治疗靶标之一，因为炎症可以 介导糖尿病并发症中的许多发病机理。在链唑霉素（STZ）的鼠模型中 - 诱导糖尿病，我们确定糖尿病介导了白介素17a（IL-17）的产生，这是其中之一 大多数与自身免疫和炎症发病机理相关的细胞因子。我们还发现IL- 17视网膜中引起的血管渗透性和毛细血管变性，这是非 - 增殖的糖尿病性视网膜病。最后，我们确定了IL-17受体和CIKS（连接到IB激酶 和应力激活的蛋白质）衔接子分子在多个视网膜细胞上组成型表达，这引起了。 视网膜炎症，氧化应激和血管病变。该提议的目的是解开IL-17 受体/CIKS信号传导事件参与视网膜发病机理，以揭示早期的新治疗靶标 糖尿病性视网膜病的发作。我们假设糖尿病会介导一系列CIKS-TRAF（TNF受体 相关因素）发起氧化应激和视网膜注射的信号传导事件，这导致 视网膜中的血管渗透性和毛细管变性。这是增殖发作的前体 糖尿病性视网膜病和视力丧失。通过使用STZ诱导的糖尿病和离体视网膜的鼠模型 测定，我们将确定CIKS-TRAF信号级联的机制，该机制进一步启动 炎症和发病机理。通过这些研究将确定治疗靶标，我们 假设将延迟糖尿病性视网膜病的发作并抑制视力丧失。