Diabetic retinopathy is a major cause of blindness in the United States. Increased expression of inflammatory molecules and death of retinal endothelial cells (capillary degeneration) with resulting local retinal ischemia are believed to be important for development of this disease. We uncovered CD40 as a major driver of the upregulation of inflammatory molecules in the retina and development of capillary degeneration in experimental diabetic retinopathy. In addition, CD40 in Mller cells triggers purinergic signaling (ATP-P2X7) that drives expression of pro-inflammatory cytokines in by-stander microglia/macrophages and programmed cell death of retinal endothelial cells. [VEGF upregulation is an event central to capillary leakage and retinal neovascularization in diabetic retinopathy. VEGF upregulation in the diabetic retina is driven by activation of the Unfolded Protein Response (UPR) in Mller cells. However, we have an incomplete understanding on how UPR is activated in the disease.] The objective of this application is to further our understanding of the [induction of UPR, the upregulation of VEGF] and inflammatory molecules in diabetic retinopathy. The central hypothesis is that a specific signaling pathway downstream of CD40 controls [UPR, VEGF upregulation and the ATP-P2X7 cascade such that selective blockade of this pathway will prevent UPR, VEGF upregulation,] inflammatory molecule upregulation, capillary degeneration and will protect against experimental diabetic retinopathy. [In the first aim we will examine how CD40 stimulates UPR in Mller cells. In the second aim we will determine if CD40 upregulates VEGF via UPR and whether the signaling pathway that mediates UPR/VEGF upregulation is different from the pathway that causes direct upregulation of inflammatory molecules in Mller cells.
Both aims will be pursued using genetic approaches that block specific signaling pathways.] In the third aim we will use an animal model of experimental diabetic retinopathy and transgenic mice to determine if [CD40 drives UPR and VEGF upregulation in vivo and whether genetic blockade of an upstream event in CD40 signaling impairs upregulation of UPR, VEGF and various inflammatory molecules in the diabetic retina.] Using similar methodologies, in the fourth aim we will test the in vivo effects of a specific inhibitor of CD40 signaling in the induction of the events described above. [The proposed work will further our understanding of UPR/VEGF upregulation in diabetic retinopathy] and may lead to further development of selective inhibitors of CD40 signaling as a novel approach for treatment of diabetic retinopathy.

Public Health Relevance

Diabetic retinopathy is a major cause of visual loss. Current therapeutic regimens do not prevent retinal damage in this disease. We plan studies that will hopefully identify a signaling pathway that can be inhibited to achieve protection against experimental diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY019250-06A1
Application #
9521114
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2010-04-01
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
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
Subauste, Carlos (2012) Animal models for Toxoplasma gondii infection. Curr Protoc Immunol Chapter 19:Unit 19.3.1-23
Subauste, Carlos S; Ajzenberg, Daniel; Kijlstra, Aize (2011) Review of the series ""Disease of the year 2011: toxoplasmosis"" pathophysiology of toxoplasmosis. Ocul Immunol Inflamm 19:297-306

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