Ischemia-reperfusion (IR) injury is implicated in a large array of pathological conditions in the retina including glaucoma, diabetic retinopathy, anterior ischemic optic neuropathy and traumatic optic neuropathy. Thus, understanding the events involved in ischemic neuronal injury can provide us with clinically effective treatments for many retinal diseases. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes in retinal function. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands liberated from injured/necrotic cells can activate TLRs, initiating an inflammatory response even in the absence of pathogens. Our published results indicate that the level of endogenous ligands for toll- like receptor 4 (TLR4) increases in retinal IR and, through activation of TLR4, are involved in retinal damage and inflammation triggered by ischemic injury. Importantly, our preliminary results suggest that the mechanisms mediating ischemic damage in the retina are facilitated not only by inflammation induced by astrocytes, microglia, or infiltrating immune cells, but also by activation of TLR4 in retinal ganglion cells (RGCs) themselves. However, the exact mechanism of TLR4 signaling-induced inflammation and damage after retinal IR injury remains unknown. In this project we hypothesize that TLR4 signaling plays a significant role in the pathogenesis of retinal IR injury by directly and/or indirectly contributing to the injury of RGCs. This hypothesis will be tested in a series of experiments outlined in the following specific aims: 1) to determine whether TLR4 coordinates the immune response of the retina to IR injury~ 2) to determine whether silencing of TLR4 signaling reduces blood retinal permeability and infiltration of leukocytes in the ischemic retina~ 3) to determine whether TLR4-mediated signals directly injure RGCs~ 4) to define the role of TLR4 ligands in the post-ischemic retina. Completion of these specific aims could lead to the discovery of innovative strategies to help prevent the loss of vision in patients suffering from retinal ischemia, as selective targeting of both TLR4 and its ligands may be more effective for the development of therapeutic tools to prevent IR injury than targeting the intracellular pathways.

Public Health Relevance

Ischemia-reperfusion (IR) injury of the retina is implicated in a large array of pathological conditions in which inflammation is a hallmark of disease. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. A greater understanding of the role of TLRs in retinal IR injury may aid in the development of specific TLR-targeted therapeutics to treat these conditions in the retina, which may be more effective for the development of therapeutic tools to prevent IR injury than targeting the intracellular pathways.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022348-03
Application #
8634102
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Chin, Hemin R
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$371,877
Indirect Cost
$126,877
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Santos, Andrea Rachelle C; Dvoriantchikova, Galina; Li, Yiwen et al. (2014) Cellular mechanisms of high mobility group 1 (HMGB-1) protein action in the diabetic retinopathy. PLoS One 9:e87574
Dvoriantchikova, Galina; Santos, Andrea Rachelle C; Saeed, Ali M et al. (2014) Putative role of protein kinase C in neurotoxic inflammation mediated by extracellular heat shock protein 70 after ischemia-reperfusion. J Neuroinflammation 11:81
Dvoriantchikova, Galina; Ivanov, Dmitry (2014) Tumor necrosis factor-alpha mediates activation of NF-?B and JNK signaling cascades in retinal ganglion cells and astrocytes in opposite ways. Eur J Neurosci 40:3171-8
Dvoriantchikova, Galina; Santos, Andrea Rachelle C; Danek, Dagmara et al. (2014) The TIR-domain-containing adapter inducing interferon-?-dependent signaling cascade plays a crucial role in ischemia-reperfusion-induced retinal injury, whereas the contribution of the myeloid differentiation primary response 88-dependent signaling cascad Eur J Neurosci 40:2502-12
Dvoriantchikova, Galina; Degterev, Alexei; Ivanov, Dmitry (2014) Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage. Exp Eye Res 123:1-7
Dvoriantchikova, Galina; Grant, Jeff; Santos, Andrea Rachelle C et al. (2012) Neuronal NAD(P)H oxidases contribute to ROS production and mediate RGC death after ischemia. Invest Ophthalmol Vis Sci 53:2823-30