Diabetes mellitus remains a leading cause of blindness world-wide and epidemiological data from the World Health Organization reveal over 422 million adults live with diabetes and the rate of disease onset continues to rise. According to the National Eye Institute 10.2 million US adults 40 years and older have diabetes mellitus, and 8.2% with vision threatening retinopathy. Macular edema remains closely linked to loss of vision and current therapies focus on mechanisms to prevent cytokine driven changes in vascular permeability that promote edema. Our previous research has fundamentally contributed to understanding the molecular mechanisms that lead to vascular endothelial growth factor (VEGF) induced retinal vessel permeability. The development of effective anti-VEGF therapies has been a welcome addition for the treatment of diabetic retinopathy, but this approach remains insufficient and new therapies are needed. In the current application we now focus on understanding the process of blood-retinal barrier regeneration. Research has identified a required role for norrin in formation of the blood-retinal barrier. Here, we explore the exciting potential for norrin to restore vascular barrier properties after VEGF-induced injury. The studies promise to shed new light on how these two critical cytokines interact to control retinal vessel barrier properties. Further, preliminary data reveal completely novel interactions of the norrin signaling molecule, disheveled (DVL), binding directly to tight junction proteins. The role of these protein interactions on norrin signaling and tight junction biology will be elucidated at a molecular level in order to understand the mechanisms of norrin action on barrier restoration. We expect this proposal will provide novel information on regulation of the blood-retinal barrier in health and in diabetes and will provide a framework from which to develop potential new therapeutic options to treat macular edema.

Public Health Relevance

Diabetes remains a major cause of vision loss in the United States and new therapies are needed. The disease process includes loss of normal retinal blood vessel barrier properties, damaging the retina and leading to loss of vision. Here, we explore the possibility of utilizing natural cytokines involved in retinal vessel development, to restore blood vessel function in models of diabetic retinopathy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Keep, Richard F; Andjelkovic, Anuska V; Xiang, Jianming et al. (2018) Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab 38:1255-1275
Dreffs, Alyssa; Henderson, Desmond; Dmitriev, Andrey V et al. (2018) Retinal pH and Acid Regulation During Metabolic Acidosis. Curr Eye Res 43:902-912
Lin, Cheng-Mao; Titchenell, Paul M; Keil, Jason M et al. (2018) Inhibition of Atypical Protein Kinase C Reduces Inflammation-Induced Retinal Vascular Permeability. Am J Pathol 188:2392-2405
Kady, Nermin M; Liu, Xuwen; Lydic, Todd A et al. (2018) ELOVL4-Mediated Production of Very Long-Chain Ceramides Stabilizes Tight Junctions and Prevents Diabetes-Induced Retinal Vascular Permeability. Diabetes 67:769-781
Ramos, Carla J; Lin, Chengmao; Liu, Xuwen et al. (2018) The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability. J Biol Chem 293:717-730
Díaz-Coránguez, Mónica; Ramos, Carla; Antonetti, David A (2017) The inner blood-retinal barrier: Cellular basis and development. Vision Res 139:123-137
Ramos, Carla J; Antonetti, David A (2017) The role of small GTPases and EPAC-Rap signaling in the regulation of the blood-brain and blood-retinal barriers. Tissue Barriers 5:e1339768
Díaz-Coránguez, Mónica; Chao, Daniel L; Salero, Enrique L et al. (2017) Cell autonomous sonic hedgehog signaling contributes to maintenance of retinal endothelial tight junctions. Exp Eye Res 164:82-89
Liu, Xuwen; Dreffs, Alyssa; Díaz-Coránguez, Monica et al. (2016) Occludin S490 Phosphorylation Regulates Vascular Endothelial Growth Factor-Induced Retinal Neovascularization. Am J Pathol 186:2486-99
Gonçalves, Andreia; Lin, Cheng-Mao; Muthusamy, Arivalagan et al. (2016) Protective Effect of a GLP-1 Analog on Ischemia-Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation. Invest Ophthalmol Vis Sci 57:2584-92

Showing the most recent 10 out of 54 publications