Diabetic retinopathy (DR), a major complication of diabetes, is the leading cause of vision impairment and loss in the working age population. Similar to other micro- and macro vascular complications of diabetes, the development and progression of DR is well documented to correlate with the duration of diabetes. This phenomenon suggests that chronic cellular stress driven by a diabetic milieu may play a role in the pathogenesis of DR. We recently discovered that endoplasmic reticulum (ER) stress is activated in the retinas of several models of diabetes. In this application, we propose to delineate the role of ER stress in DR. We hypothesize that diabetes-induced ER stress promotes inflammation and is thereby a central driving force inducing retinal pathology leading to DR (e.g. breakdown of the blood-retinal barrier, capillary cell death, and aberrant new vessel growth in the retina). We plan to use complementary in vitro and in vivo experiments, pharmaceutical and genetic interventions, and state-of-art techniques to test our hypothesis.
In Aim 1, we will fully characterize ER stress and the unfolded protein response (UPR), a protective mechanism of the ER, in the retinas of two different models of diabetes and address how diabetes causes retinal ER stress and alters the UPR.
In Aim 2, we propose to study the therapeutic effects and mechanism of action of X-box binding protein 1 (XBP1), an endogenous ER stress inhibitor, in mitigating retinal inflammation and reducing the vascular pathology associated with DR.
In Aim 3, using newly generated cell-specific XBP1 knockout mouse models, we will delineate the role of ER stress in specific retinal cell types and to establish the importance of endogenous XBP1 in counteracting ER stress and inflammation and protecting retinal vascular cells from diabetic damage. In summary, the proposed studies will establish the central role of ER stress and the importance of the UPR in the development of diabetes-driven inflammation and retinal vascular pathology. In addition, this work will establish the therapeutic potential of a novel protective agent to block the onset and/or progression of DR, a disease that is approaching epidemic proportions in the US. The outcomes may also impact other vision-threatening diseases in which ER stress is potentially implicated, such as age-related macular degeneration (AMD).

Public Health Relevance

Diabetic retinopathy (DR), a major complication of diabetes, is a leading cause of vision impairment and loss in the working age population. The goals of this grant application are to delineate the role of endoplasmic reticulum (ER) stress in the development of retinal vascular pathology in diabetes, and to test the therapeutic potential of a novel protective agent in counteracting ER stress and inflammatory damage of retinal cells in DR. The realization of these goals is anticipated to identify a novel mechanism underpinning the retinal complications of diabetes and pave the way for new therapies to prevent/treat this sight-threatening disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019949-06
Application #
8723215
Study Section
Biology and Diseases of the Posterior Eye (BDPE)
Program Officer
Shen, Grace L
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Schools of Medicine
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Ma, Jacey Hongjie; Shen, Shichen; Wang, Joshua J et al. (2017) Comparative Proteomic Analysis of the Mitochondria-associated ER Membrane (MAM) in a Long-term Type 2 Diabetic Rodent Model. Sci Rep 7:2062
Ma, Jacey H; Wang, Joshua J; Li, Junhua et al. (2016) The Role of IRE-XBP1 Pathway in Regulation of Retinal Pigment Epithelium Tight Junctions. Invest Ophthalmol Vis Sci 57:5244-5252
Boriushkin, Evgenii; Wang, Joshua J; Li, Junhua et al. (2016) p58(IPK) suppresses NLRP3 inflammasome activation and IL-1? production via inhibition of PKR in macrophages. Sci Rep 6:25013
Huang, Chuangxin; Wang, Joshua J; Ma, Jacey H et al. (2015) Activation of the UPR protects against cigarette smoke-induced RPE apoptosis through up-regulation of Nrf2. J Biol Chem 290:5367-80
Bhatta, Maulasri; Ma, Jacey Hongjie; Wang, Joshua J et al. (2015) Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes. Diabetologia 58:2181-90
Huang, Huibin; Jing, Guangjun; Wang, Joshua J et al. (2015) ATF4 is a novel regulator of MCP-1 in microvascular endothelial cells. J Inflamm (Lond) 12:31
Li, Jingming; Wang, Joshua J; Zhang, Sarah X (2015) NADPH oxidase 4-derived H2O2 promotes aberrant retinal neovascularization via activation of VEGF receptor 2 pathway in oxygen-induced retinopathy. J Diabetes Res 2015:963289
Boriushkin, Evgenii; Wang, Joshua J; Li, Junhua et al. (2015) Identification of p58IPK as a novel neuroprotective factor for retinal neurons. Invest Ophthalmol Vis Sci 56:1374-86
McLaughlin, Todd; Zhang, Sarah X (2015) The neuroprotective potential of endoplasmic reticulum chaperones. Neural Regen Res 10:1211-3
Tryggestad, Jeanie B; Wang, Joshua J; Zhang, Sarah X et al. (2015) Elevated plasma pigment epithelium-derived factor in children with type 2 diabetes mellitus is attributable to obesity. Pediatr Diabetes 16:600-5

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