PKA and Epac1 inhibit TLR4 to protect the diabetic retina

PKA和Epac1抑制TLR4以保护糖尿病视网膜

• 批准号: 10554345
• 负责人: Jena J Steinle
• 金额: $ 35.13万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554345
• 关键词: Adrenergic Agents; Adult; Age; Agonist; Biological Assay; Blindness; Blood Vessels; Cells; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Disease Progression; Down-Regulation; Early treatment; Endothelial Cells; Forskolin; Glucose; Goals; Immunity; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Macrophage; Mediating; Mediator; Molecular; Muller' s cell; Mus; Natural Immunity; Neurons; Pathway interactions; Pattern; Permeability; Phase; Process; Proteins; Receptor Activation; Regulation; Reporting; Retina; Role; Signal Transduction; Small Interfering RNA; Streptozocin; TLR2 gene; TLR4 gene; Testing; Toll-like receptors; Work; beta-adrenergic receptor; chemokine; conditional knockout; cytokine; diabetic; diabetic rat; improved; in vivo; inflammatory marker; inhibitor; knock-down; macular edema; new therapeutic target; novel; novel therapeutics; overexpression; pharmacologic; prevent; receptor; response; retinal damage; targeted treatment; therapeutic development; therapeutically effective; therapy development

Diabetic retinopathy is the leading cause of blindness in working age adults; however, much of this blindness occurs in the later phases of the disease due to proliferative disease or macular edema. Recently, the role of inflammation has become a focus of potential therapies targeted to treat earlier stages and/or prevent progression of the disease. While it is clear that a large number of cytokines/chemokines are increased in the diabetic retina, the role of innate immunity has only recently been investigated. Recent work has demonstrated that toll-like receptors (TLRs) are altered in diabetes. Work has also shown that TLR4 is increased in the streptozotocin-induced diabetic retina. Additionally, TLR4 may have actions in retinal endothelial cells (REC), as both TLR2/4 pathways are active in these retinal cells. Our preliminary data has expanded on those findings to demonstrate that β-adrenergic receptors can decrease TLR4 signaling in the diabetic mouse retina, as well as in both REC and retinal Müller cells. Supporting our findings in retina, studies in macrophages also demonstrate that β-adrenergic receptors can regulate TLR4. The response to Compound 49b was blocked when Epac1 or PKA were knocked down by siRNA, suggesting these proteins act as damage associated molecular pattern molecules (DAMPs) regulating TLR4 signaling in the diabetic retina. Our primary hypothesis for this proposal is that PKA and Epac1 can regulate TLR4 and may represent a key pathway that controls retina damage in diabetes. Our overall goal is to better understand the role of downstream mediators of β-adrenergic receptors in the regulation of TLR4 signaling in the diabetic retina, with the intent of identifying key pathways in innate immunity that can be targeted for novel therapeutics. !

糖尿病视网膜病变是工作年龄成年人失明的主要原因；然而，这种失明的很大一部分 由于增殖性疾病或黄斑水肿而发生在疾病的后期。最近，他扮演的角色 炎症已成为潜在治疗方法的焦点，旨在治疗早期和/或预防 疾病的发展。虽然很明显，大量的细胞因子/趋化因子在 糖尿病视网膜，先天免疫的作用直到最近才被研究。最近的工作有 研究表明，糖尿病患者的Toll样受体(TLRs)会发生改变。研究还表明，TLR4是 在链脲佐菌素诱导的糖尿病视网膜中增加。此外，TLR4可能在视网膜中起作用 内皮细胞(REC)，因为这两个TLR2/4通路在这些视网膜细胞中都是活跃的。我们的初步数据显示 在这些发现的基础上展开，以证明β-肾上腺素能受体可以减少TLR4信号在 糖尿病小鼠视网膜，以及视网膜内皮细胞和视网膜Müler细胞。支持我们在视网膜上的发现， 巨噬细胞的研究还表明，β-肾上腺素能受体可以调节TLR4。对以下问题的回应 当Epac1或PKA被siRNA击倒时，化合物49b被阻断，这表明这些蛋白质起作用 作为损伤相关的分子模式分子(DAMP)，调节糖尿病视网膜中的TLR4信号。 我们对这一提议的主要假设是，PKA和Epac1可以调节TLR4，并可能代表一个关键 控制糖尿病视网膜损伤的途径。我们的总体目标是更好地理解 β-肾上腺素能受体在糖尿病视网膜中调节TLR4信号的下游介体 目的是确定先天免疫的关键途径，这些途径可以作为新疗法的靶点。 好了！