Diabetic retinopathy is a major cause of blindness in the United States. Upregulation of adhesion molecules, chemokines, nitric oxide synthase (NOS2), inducible cyclooxygenase (COX-2) and vascular endothelial growth factor (VEGF) are pro- inflammatory responses believed to be important in this disease. It is increasingly recognized that these responses contribute to retinal injury and neuro-vascular degeneration. Understanding the regulation of these responses is important because neuronal death largely contributes to visual loss in diabetic retinopathy and currently available treatment regimens have not been able to prevent neuronal loss. The objective of this application is to further our understanding of the regulation of pro-inflammatory responses and neuro-vascular degeneration in diabetic retinopathy. The central hypothesis for the proposed research is that there is a previously unrecognized upstream molecule that triggers the pro-inflammatory responses mentioned above and mediates neuro-vascular degeneration in diabetic retinopathy. Finding that a single molecule controls various cellular responses involved in the pathogenesis of this disease would be significant because it would suggest that targeting a single molecule would impair multiple pro-retinopathy factors. In the first specific aim we will characterize the regulation of pro-inflammatory responses in retinal microglia, Muller cells and endothelial cells. This will be accomplished using immunological assays and gene transfer approaches that block specific signaling proteins. In addition, we will test whether a novel approach to deliver molecules intra-cellularly can be used to block signaling that controls pro-inflammatory responses in retinal cells. Using similar methodologies, in the second specific aim we will characterize the regulation of neuronal and endothelial cell death caused by these pro-retinopathy responses. Using an animal model of diabetic retinopathy in wild-type and knock-out mice we will evaluate the in vivo effects of regulation of inflammation on the development of diabetic retinopathy. The proposed work may lead to new strategies to treat diabetic retinopathy.

Public Health Relevance

Diabetic retinopathy is a major cause of visual loss. Current therapeutic regimens do not prevent tissue injury and neuronal damage in this disease. We plan studies that will hopefully identify molecules that can be manipulated to achieve neuro-protection in patients with this retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019250-04
Application #
8461196
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mckie, George Ann
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$322,164
Indirect Cost
$116,964
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Samuels, Ivy S; Portillo, Jose-Andres C; Miao, Yanling et al. (2017) Loss of CD40 attenuates experimental diabetes-induced retinal inflammation but does not protect mice from electroretinogram defects. Vis Neurosci 34:E009
Portillo, Jose-Andres C; Lopez Corcino, Yalitza; Miao, Yanling et al. (2017) CD40 in Retinal Müller Cells Induces P2X7-Dependent Cytokine Expression in Macrophages/Microglia in Diabetic Mice and Development of Early Experimental Diabetic Retinopathy. Diabetes 66:483-493
Greene, Jennifer A; Portillo, Jose-Andres C; Lopez Corcino, Yalitza et al. (2015) CD40-TRAF Signaling Upregulates CX3CL1 and TNF-? in Human Aortic Endothelial Cells but Not in Retinal Endothelial Cells. PLoS One 10:e0144133
Portillo, Jose-Andres C; Greene, Jennifer A; Schwartz, Isaac et al. (2015) Blockade of CD40-TRAF2,3 or CD40-TRAF6 is sufficient to inhibit pro-inflammatory responses in non-haematopoietic cells. Immunology 144:21-33
Portillo, Jose-Andres C; Schwartz, Isaac; Zarini, Simona et al. (2014) Proinflammatory responses induced by CD40 in retinal endothelial and Müller cells are inhibited by blocking CD40-Traf2,3 or CD40-Traf6 signaling. Invest Ophthalmol Vis Sci 55:8590-7
Portillo, Jose-Andres C; Greene, Jennifer A; Okenka, Genevieve et al. (2014) CD40 promotes the development of early diabetic retinopathy in mice. Diabetologia 57:2222-31
Cheng, Lijia; Bu, Hong; Portillo, Jose-Andres C et al. (2013) Modulation of retinal Müller cells by complement receptor C5aR. Invest Ophthalmol Vis Sci 54:8191-8
Portillo, Jose-Andres C; Feliciano, Luis Muniz; Okenka, Genevieve et al. (2012) CD40 and tumour necrosis factor-? co-operate to up-regulate inducuble nitric oxide synthase expression in macrophages. Immunology 135:140-50
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