Transforming Growth Factor Beta-Activated Kinase 1 (Tak1) in Retinal Microglial Inflammation

转化生长因子 β 激活激酶 1 (Tak1) 在视网膜小胶质细胞炎症中的作用

• 批准号: 10438002
• 负责人: TERI L BELECKY-ADAMS
• 金额: $ 45.6万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438002
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Astrocytes; B-Cell Activation; Blood flow; Blood-Retinal Barrier; Brain; Brain region; Carbon Dioxide; Cell Count; Cells; Cerebrovascular Circulation; Chronic; Complement Factor B; Complication; Critical Pathways; Data; Diabetes Mellitus; Diabetic Retinopathy; Disease; Elements; Endothelial Cells; Enhancers; Ensure; Enzyme-Linked Immunosorbent Assay; Failure; Genetic Transcription; Goals; HMGB1 Protein; Health; Heterogeneity; IL6 gene; Immune; Immunologic Surveillance; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interleukin-6; Knock-out; Laboratories; Lead; Ligands; Light; MAP3K7 gene; MAPK8 gene; Measurement; Measures; Mediating; Messenger RNA; Metabolic; Microglia; Microinjections; Muller' s cell; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropil; Nuclear; Nutrient; Oxygen; Parkinson Disease; Pathway interactions; Pericytes; Pharmacologic Substance; Phosphotransferases; Play; Polymerase Chain Reaction; Population; Positioning Attribute; Process; Proteins; Research Personnel; Retina; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Streptozocin; Supporting Cell; TNF gene; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Type 2 diabetic; Up-Regulation; Western Blotting; astrogliosis; cohort; diabetic patient; experimental study; factor A; ganglion cell; glymphatic system; in vitro testing; in vivo; inhibitor; macroglia; member; neurovascular unit; new therapeutic target; p38 Mitogen Activated Protein Kinase; small molecule inhibitor; therapeutic target; type I diabetic; wasting

Diabetic retinopathy is associated with chronic aberrant inflammation that is proposed to play a critical role in the early disruption of neurovascular unit function. There is incomplete information about intracellular signaling pathways involved in upregulation of inflammatory signals. Identification of more pathway members will lead to more therapeutic targets to be used in treatment of neurodegenerative diseases. This proposal is aimed at testing the role of transforming growth factor β-activated kinase 1 (TAK1) in activation NFκB, p38, and JNK pathways in retinal microglia, resulting in increased transcription of inflammatory factors. The hypothesis that inhibition of TAK1 will reduce inflammation in the early stages of diabetic retinopathy and reduce changes to the neurovascular unit will be tested in vitro using isolated microglial cells and in vivo using a combination of streptozotocin (STZ)-induced diabetes in mice with conditional loss of TAK1 in microglia. Experiments will utilize small molecule inhibitors, addition of known inflammatory factors, microinjections, quantitative polymerase chain reactions, Western blot analysis, multiplex enzyme-linked immunosorbent assays, and quantitation of pericytes, microvasculature, microglia, retinal astrocytes, ganglion cells, and Müller glia in retinal wholemounts and sections.

糖尿病视网膜病变与慢性异常炎症有关，据认为，慢性异常炎症在糖尿病视网膜病变中发挥着关键作用。 神经血管单元功能的早期破坏 关于细胞内信号传导的信息不完整。 涉及炎症信号上调的途径将导致更多途径成员的鉴定。 该提案旨在用于治疗神经退行性疾病的更多治疗靶点。 测试转化生长因子 β 激活激酶 1 (TAK1) 在激活 NFκB、p38 和 JNK 中的作用 视网膜小胶质细胞中的通路，导致炎症因子转录增加。 抑制 TAK1 将减少糖尿病视网膜病变早期阶段的炎症，并减少糖尿病视网膜病变的变化 神经血管单元将使用分离的小胶质细胞进行体外测试，并使用以下组合进行体内测试 实验将在小胶质细胞中条件性丧失 TAK1 的小鼠中使用链脲佐菌素 (STZ) 诱导糖尿病。 利用小分子抑制剂，添加已知的炎症因子，显微注射，定量 聚合酶链反应、蛋白质印迹分析、多重酶联免疫吸附测定以及 视网膜中周细胞、微血管、小胶质细胞、视网膜星形胶质细胞、神经节细胞和穆勒胶质细胞的定量 整体和部分。