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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

基本信息

批准号：
10320378
负责人：
Jena J Steinle
金额：
$ 34.07万
依托单位：
WAYNE STATE UNIVERSITY
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：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320378
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 Mediating Mediator of activation protein Molecular Muller&apos s cell Mus Natural Immunity Neurons Pathway interactions Pattern Permeability Pharmacology 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 macrophage macular edema new therapeutic target novel novel therapeutics overexpression prevent receptor response retinal damage targeted treatment therapeutic development therapeutically effective therapy development

项目摘要

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导致工作年龄成年人失明的主要原因;然而，由于增殖性疾病或黄斑水肿而发生在疾病的后期。最近，炎症已经成为靶向治疗早期阶段和/或预防炎症的潜在疗法的焦点疾病的进展。虽然清楚的是，大量的细胞因子/趋化因子在肿瘤细胞中增加，但是，在肿瘤细胞中，细胞因子/趋化因子的表达增加，而在肿瘤细胞中，细胞因子/趋化因子的表达增加。在糖尿病视网膜中，先天免疫的作用只是最近才被研究。最近的工作已经 Toll样受体（TLR）在糖尿病中发生改变。研究还表明，TLR 4是链脲佐菌素诱导的糖尿病视网膜中增加。另外，TLR 4可能在视网膜神经元中起作用。内皮细胞（REC），因为TLR 2/4途径在这些视网膜细胞中都很活跃。我们的初步数据显示扩展了这些发现，证明β-肾上腺素能受体可以减少TLR 4信号在糖尿病小鼠视网膜，以及REC和视网膜Müller细胞。支持我们在视网膜上的发现，在巨噬细胞中的研究也证明β-肾上腺素能受体可以调节TLR 4。应对当Epac 1或PKA被siRNA敲低时，化合物49 b被阻断，表明这些蛋白质起作用。作为糖尿病视网膜中调节TLR 4信号传导的损伤相关分子模式分子（DAMP）。我们对这一提议的主要假设是PKA和Epac 1可以调节TLR 4，并且可能代表了一个关键因素，控制糖尿病视网膜损伤的途径。我们的总体目标是更好地了解 β-肾上腺素能受体的下游介质在糖尿病视网膜中调节TLR 4信号传导，目的是鉴定先天免疫中可作为新疗法靶向的关键途径。 !