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

糖尿病视网膜病变与慢性异常炎症有关，慢性异常炎症在糖尿病视网膜病变中起关键作用

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.