Spectral Domain Optical Coherence Tomography in Mouse Models of Retinal Degeneration

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

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“…SLO imaging (Heidelberg Engineering) was performed for in vivo whole-fundus imaging of mouse retinas (84). Mice were anesthetized by i.p.…”

Section: Methodsmentioning

confidence: 99%

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

et al. 2013

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“…For more than a decade, in vivo longitudinal imaging has been reliably performed in experimental rodent models of optic nerve damage causing RGC loss. Commonly used methods include fluorescence imaging of retrogradely labelled RGCs, 26,27 structural imaging of the optic nerve head [28][29][30][31] or axons, 32 and imaging of RGC apoptosis. 33 Of particular interest is the ability to image living RGC somas expressing fluorescent proteins.…”

Section: Tracking Retinal Ganglion Cells In Vivomentioning

confidence: 99%

Assessing retinal ganglion cell damage

Smith

Vianna

Chauhan

2017

Eye

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Retinal ganglion cell (RGC) loss is the hallmark of optic neuropathies, including glaucoma, where damage to RGC axons occurs at the level of the optic nerve head. In experimental glaucoma, damage is assessed at the axon level (in the retinal nerve fibre layer and optic nerve head) or at the soma level (in the retina). In clinical glaucoma where measurements are generally limited to non-invasive techniques, structural measurements of the retinal nerve fibre layer and optic nerve head, or functional measurements with perimetry provide surrogate estimates of RGC integrity. These surrogate measurements, while clinically useful, are several levels removed from estimating actual RGC loss. Advances in imaging, labelling techniques, and transgenic medicine are making enormous strides in experimental glaucoma, providing knowledge on the pathophysiology of glaucoma, its progression and testing new therapeutic avenues. Advances are also being made in functional imaging of RGCs. Future efforts will now be directed towards translating these advances to clinical care.

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“…Recently, two kinds of noninvasive retinal imaging modalities, scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT), have been successfully applied to monitor structural changes in the retinas of individual mice in longitudinal studies. [1][2][3][4][5][6][7][8] SLO is a common diagnostic imaging technique in ophthalmology 9,10 and can generate images from retinal reflectance, autofluorescence, and extrinsic fluorescence. At the same time, the confocal arrangement helps SLO reject scattered light and improve image contrast, and potentially achieve moderate depth sectioning.…”

Section: Introductionmentioning

confidence: 99%

In vivowide-field multispectral scanning laser ophthalmoscopy–optical coherence tomography mouse retinal imager: longitudinal imaging of ganglion cells, microglia, and Müller glia, and mapping of the mouse retinal and choroidal vasculature

et al. 2015

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Abstract. Scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) provide complementary views of the retina, with the former collecting fluorescence data with good lateral but relatively lowaxial resolution, and the latter collecting label-free backscattering data with comparable lateral but much higher axial resolution. To take maximal advantage of the information of both modalities in mouse retinal imaging, we have constructed a compact, four-channel, wide-field (∼50 deg) system that simultaneously acquires and automatically coregisters three channels of confocal SLO and Fourier domain OCT data. The scanner control system allows "zoomed" imaging of a region of interest identified in a wide-field image, providing efficient digital sampling and localization of cellular resolution features in longitudinal imaging of individual mice. The SLO is equipped with a "flip-in" spectrometer that enables spectral "fingerprinting" of fluorochromes. Segmentation of retina layers and en face display facilitate spatial comparison of OCT data with SLO fluorescence patterns. We demonstrate that the system can be used to image an individual retinal ganglion cell over many months, to simultaneously image microglia and Müller glia expressing different fluorochromes, to characterize the distinctive spatial distributions and clearance times of circulating fluorochromes with different molecular sizes, and to produce unequivocal images of the heretofore uncharacterized mouse choroidal vasculature. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Spectral Domain Optical Coherence Tomography in Mouse Models of Retinal Degeneration

Cited by 179 publications

References 36 publications

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

Assessing retinal ganglion cell damage

In vivowide-field multispectral scanning laser ophthalmoscopy–optical coherence tomography mouse retinal imager: longitudinal imaging of ganglion cells, microglia, and Müller glia, and mapping of the mouse retinal and choroidal vasculature

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