Diabetes, a global epidemic of the 21st century, affects 285 millions worldwide. The overwhelming cause of vision loss in diabetics is macular edema (DME) that is characterized by alteration of the blood-retinal barrier. Despite the use of molecular therapeutics targeting vascular endothelial growth factor (VEGF), the majority of patients do not recover good, functional vision, and show residual edema, necessitating repeated intravitreal injections. The scientific gap is due to the present inability to completely block all the inflammatory mediators implicated in the pathogenesis of DME. Evidence suggests that diabetic retinopathy is an inflammatory disease. The precise mechanism by which the chemokines and leukocytes initiate the inflammatory cascade and finally damages this barrier is not clear. Our preliminary findings show that CC chemokines (CCL2, 5 and 7) are significantly up regulated in the retinas of diabetic animals. Also, there is increased trafficking of monocytes into the retina along with activation of retinal microglia in diabetes. Studies using CCL2 gene- deficient mice made diabetic show significantly less retinal vascular leakage, indicating the important role of this chemokine in alteration of the blood-retinal barrier. These findings define chemokines as a novel specific molecular therapeutic target in diabetic retinopathy. Our central hypothesis is that increased inflammatory CC chemokines in the diabetic retina alter the blood-retinal barrier through the recruitment of immune cells. This hypothesis will be tested in three specific aims. i) In this proposal, we will characterize CCL2 and its receptor expression in the retina of diabetic animals, and in isolated retinal cells using cellular and molecular approaches. We will validate expression of chemokines and receptors in human donor eyes, correlate chemokine levels in serum of patients with different stages of human diabetic retinopathy and use chemokines as an early diagnostic bio-marker. ii) We will determine the molecular mechanisms by which the CCL2 and immune cells alter the blood-retinal barrier in diabetes in cooperation with other factors like angiopoietin-2 and proteinases. iii) We will further validate targeting of the CCL2 pathway as a therapeutic strategy in a diabetic animal model to prevent or reverse the alteration of the blood-retinal barrier. The chemokine pathway is critical in orchestrating the influx of leukocytes in diabetic retinopathy ultimately leading to macular edema, and is an excellent future target for the treatment of this devastating blindness. This approach is innovative as it addresses a novel mechanism of stabilizing the initial step of leukocyte-endothelial interaction, the critical upstream bottleneck for diabetic macular edema. This proposed research project is significant as it can transform the clinical practice paradigm by introducing a novel therapy using chemokines as targets, and a potential biomarker in early identification of patients with DME. Successful completion of this project will have the high translational impact for a clinical trial for DME, and potentially lead to a """"""""combination therapy"""""""" along with the current laser and anti-VEGF therapies.
Diabetic macular edema is the most common cause of moderate vision loss in diabetics. This proposal can transform the clinical practice paradigm by introducing a novel therapy using chemokines as targets, and a potential biomarker in early identification of patients with DME. The focus of our research is compatible with the mission of the NIH in understanding the molecular mechanisms of a global epidemic, and in evolving new directions related to diagnosis and treatment of diabetic retinopathy.
|Yang, Xiao; Scott, Harry A; Monickaraj, Finny et al. (2016) Basement membrane stiffening promotes retinal endothelial activation associated with diabetes. FASEB J 30:601-11|
|Monickaraj, Finny; McGuire, Paul G; Nitta, Carolina Franco et al. (2016) Cathepsin D: an MÏ•-derived factor mediating increased endothelial cell permeability with implications for alteration of the blood-retinal barrier in diabetic retinopathy. FASEB J 30:1670-82|
|Rangasamy, Sampathkumar; McGuire, Paul G; Franco Nitta, Carolina et al. (2014) Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy. PLoS One 9:e108508|