Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy

Furtado, João M.; Davies, M.; Choi, Dongseok; Lauer, Andreas K.; Appukuttan, Binoy; Bailey, Steven T.; Rahman, Hassan; Payne, John F.; Stempel, Andrew J.; Mohs, Kathleen; Powers, Michael R.; Yeh, Steven; Smith, Justine R.

doi:10.1167/tvst.1.2.5

Cited by 10 publications

(8 citation statements)

References 25 publications

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“…Topical endoscopy fundus imaging (TEFI), a technique developed by Paques et al that provides high-resolution digital photographs of the retina in live mice, 92 has been recently adapted for use in the mouse OIR model. 93 Although the earliest time point that TEFI can detect retinal vascular changes is at P15, the images obtained reflect disease course that is consistent with conventional methods of assessment, and a 5-point grading system developed by Furtado et al demonstrates reasonable intra- and interobserver reliability. 93 The use of TEFI provides the opportunity to perform multiple retinal examinations in the same mouse to track disease course.…”

Section: Limitations Of the Mouse Model Of Oirmentioning

confidence: 63%

Revisiting the mouse model of oxygen-induced retinopathy

Kim

D'Amore

Connor

2016

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Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR) has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress.

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Section: Limitations Of the Mouse Model Of Oirmentioning

confidence: 63%

Revisiting the mouse model of oxygen-induced retinopathy

Kim

D'Amore

Connor

2016

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“…Genteal ® gel (Novartis) was applied over the cornea. Fundus images were captured (adapted from (23)) with a system consisting of: a tripod-mounted Nikon D90 camera, 60 mm F/2.8 D lens (Nikon), Storz 481C halogen light (Karl Storz), and Storz 1218 tele-otosope (Karl Storz). Clinical disease severity was assessed in masked fashion using a previously defined scoring system (22, 24) ranging from 0 (no disease) to 4 (maximal disease) based on the extent of vasculitis, infiltrative lesions, optic disc inflammation, retinal hemorrhages, and retinal detachment.…”

Section: Methodsmentioning

confidence: 99%

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye

Lee

Brown

Vance

et al. 2016

The Journal of Immunology

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Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or non-infectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoceptor retinoid binding protein (IRBP) in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated antigen-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2 and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease.

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“…Ocular fundus exams were performed under inhalation of isoflurane anesthesia using topical endoscopic fundus imaging (TEFI) as previously described (22–24). …”

Section: Methodsmentioning

confidence: 99%

Blau Syndrome–Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice

Dugan

Griffiths

Snow

et al. 2015

The Journal of Immunology

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The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) cause Blau syndrome is unknown. Several studies have examined the effect of mutations associated with Blau syndrome in vitro, but none have looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau syndrome, R314Q (corresponding to R334Q in humans). The endogenous regulatory elements of mouse Nod2 were unaltered. R314Q mice showed reduced cytokine production in response to i.p. and intravitreal muramyl dipeptide (MDP). Macrophages from R314Q mice showed reduced NF-κB and IL-6 responses, blunted phosphorylation of MAPKs, and deficient ubiquitination of receptor-interacting protein 2 in response to MDP. R314Q mice expressed a truncated 80 kDa form of NOD2 that was most likely generated by a posttranslational event since there was no evidence for a stop codon or alternative splicing event. Human macrophages from 2 patients with Blau syndrome also showed a reduction of both cytokine production and phosphorylation of p38 in response to MDP, indicating that both R314Q mice and cells from patients with Blau syndrome show reduced responses to MDP. These data indicate that the R314Q mutation when studied with the Nod2 endogenous regulatory elements left intact is associated with marked structural and biochemical changes that are significantly different from those observed from studies of the mutation using over-expression, transient transfection systems.

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Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy

Abstract: Topical endoscopy fundus imaging has application in the evaluation of novel biologic drugs for retinopathy of prematurity.

Cited by 10 publications

References 25 publications

Revisiting the mouse model of oxygen-induced retinopathy

Revisiting the mouse model of oxygen-induced retinopathy

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye

Blau Syndrome–Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice

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