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：
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
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/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&apos 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

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. !

糖尿病性视网膜病是成年成年人失明的主要原因。但是，大部分失明由于疾病增殖或黄斑水肿，发生在疾病的后期。最近，炎症已成为用于治疗早期阶段和/或预防的潜在疗法的重点疾病的进展。虽然很明显，大量的细胞因子/趋化因子在糖尿病性视网膜，天生免疫的作用直到最近才研究。最近的工作有证明糖尿病中的Toll样受体（TLR）改变了。工作还表明TLR4是链蛋白酶诱导的糖尿病性视网膜中的增加。此外，TLR4可能在视网膜中采取行动内皮细胞（REC），因为TLR2/4途径在这些残留细胞中均活跃。我们的初步数据扩展了这些发现，以证明β-肾上腺素受体可以降低TLR4信号传导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。对当siRNA击倒EPAC1或PKA时，化合物49b被阻断，表明这些蛋白质作用作为损伤相关的分子模式分子（湿），调节糖尿病性视网膜中TLR4信号传导。我们对该提案的主要假设是PKA和EPAC1可以调节TLR4，并且可能代表关键控制糖尿病中视网膜损害的途径。我们的总体目标是更好地了解在糖尿病视网膜中TLR4信号传导调控中，β-肾上腺素受体的下游介体，目的是鉴定有针对新治疗的先天免疫中的关键途径。呢