The role of IL-17 neutrophils and lymphocytes during diabetic retinopathy

IL-17 中性粒细胞和淋巴细胞在糖尿病视网膜病变中的作用

• 批准号: 9137364
• 负责人: Patricia R Taylor
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137364
• 关键词: Address; Apoptotic; Autoimmune Diseases; Binding; Biological Assay; Blindness; Blood capillaries; Cardiovascular Diseases; Caring; Cell Death; Cells; Chronic; Clinical; Communities; Complex; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diagnosis; Disease; Drug Targeting; Endothelial Cells; Epidemic; Event; Functional disorder; Goals; Hyperglycemia; IL17 gene; Immune response; Immune system; Immunoblot Analysis; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Interleukin-7; Interleukins; Intervention; Kidney Diseases; Laboratories; Lead; Lymphocyte; Mediating; Mus; Nature; Oxidative Stress; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Peptide Hydrolases; Peptide Signal Sequences; Play; Population; Prediabetes syndrome; Process; Production; Proteins; Reactive Oxygen Species; Receptor Signaling; Reporting; Research Project Grants; Research Proposals; Retina; Retinal; Retinal Diseases; Role; STAT3 gene; Signal Transduction; Source; Streptozocin; System; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Treatment Cost; Vascular Permeabilities; Veterans; Visual; autocrine; base; capillary; chemokine; clinically relevant; cytokine; diabetic; immunoregulation; in vivo; inhibitor/antagonist; mouse model; neutrophil; novel; novel therapeutics; prevent; public health relevance; receptor; small molecule; small molecule inhibitor; therapeutic target; transcription factor

 DESCRIPTION (provided by applicant): Currently, 30 million people have been diagnosed with diabetes, with an additional 86 million being treated for pre-diabetes, and this epidemic continues to rise annually in the US. Beyond this, one in every four Veterans receiving care from the VA is being treated for diabetes and its many physical complications, with almost half suffering from diabetic retinopathy, which is the leading cause of blindness in the US. With such a significant impact on both the US and the Veteran community, new therapeutics is required to stay abreast of the financial and physical threat posed by this visual disease. One of the most promising sources of such a therapeutic target lies within the immune system. The alteration of the immune system mediates much of the pathogenesis in diabetic complications through protein cytokine production, with IL-17 being the most prevalent cytokine in inflammatory disorders and diabetes. This research project will focus on the role of IL-17 in diabetic retinopathy, and will be the first study to characterize IL-7 producing neutrophils in diabetes. IL-17 producing neutrophils will be a major focus in this study because they are the only cell in the immune system that has an autocrine IL- 17 function that increases production of pro-inflammatory chemokines, proteinases, and reactive oxygen species, which likely play a role in diabetic retinopathy. Murine models of diabetic retinopathy will be used to test the hypothesis that diabetes alters the immune system, promoting IL-17 production by neutrophils and lymphocytes, which lead to chronic inflammation, oxidative stress, and development of clinical retinopathy. Further, through these studies potential therapeutic targets will be identified to immunomodulate IL-17 production and delay the onset of retinal pathology.

 描述（由申请人提供）： 目前，有3000万人被诊断患有糖尿病，另有8600万人正在接受糖尿病前期治疗，并且这种流行病在美国每年继续上升。除此之外，每四名接受VA护理的退伍军人中就有一人正在接受糖尿病及其许多身体并发症的治疗，其中近一半患有糖尿病视网膜病变，这是美国失明的主要原因。由于对美国和退伍军人社区都有如此重大的影响，需要新的治疗方法来跟上这种视觉疾病所带来的经济和身体威胁。这种治疗靶点的最有希望的来源之一在于免疫系统。免疫系统的改变通过蛋白质细胞因子的产生介导糖尿病并发症中的大部分发病机制，其中IL-17是炎性病症和糖尿病中最普遍的细胞因子。该研究项目将重点关注IL-17在糖尿病视网膜病变中的作用，并将是第一项表征糖尿病中产生IL-7的中性粒细胞的研究。产生IL-17的中性粒细胞将是本研究的主要焦点，因为它们是免疫系统中唯一具有自分泌IL- 17功能的细胞，该功能增加促炎趋化因子、蛋白酶和活性氧的产生，这些可能在糖尿病视网膜病变中发挥作用。糖尿病视网膜病变的鼠模型将用于检验以下假设：糖尿病改变免疫系统，促进中性粒细胞和淋巴细胞产生IL-17，从而导致慢性炎症、氧化应激和临床视网膜病变的发展。此外，通过这些研究，将确定潜在的治疗靶点，以免疫调节IL-17的产生并延迟视网膜病变的发作。