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Frontier Research on Retina

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 23626

Special Issue Editors


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Guest Editor
Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL 60637, USA
Interests: age-related macular degeneration; diabetic retinopathy; central serous retinopathy; choroidal melanoma; retinoblastoma; retinal detachment; proliferative vitreoretinopathy; retinopathy of prematurity; posterior uveitis; inherited retinal diseases; macular hole; epiretinal membrane; retinal vein occlusion
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Guest Editor
1. Eyevensys, 11 Rue Watt, 75013 Paris, France
2. Centre de Recherche des Cordeliers, INSERM, Université de Paris Cité, Sorbonne Université, From Physiopathology of Ocular Diseases to Clinical Development, 75006 Paris, France
3. Cochin Hospital, AP-HP, Assistance Publique Hôpitaux de Paris, 24 rue du Faubourg Saint Jacques, 75014 Paris, France
Interests: neuroprotection; diabetic retinopathy; retinal ischemia; glia; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in molecular techniques such as high-throughput and single-cell RNA sequencing, genetics, microbiomics, metabolomics, iPS cells, in combination with advanced retina imaging, Big Data, and advanced bioinformatics analysis-network medicine have introduced powerful new tools for novel frontiers in retinal research. These exciting new cutting-edge technologies were not available to most of us just a decade ago, but these new tools will lead to a new era of elucidating the molecular mechanisms of retinal disorders and discovery of new targets and therapeutic strategies. The purpose of this Special Issue is to highlight recent and novel frontiers in retinal research. In this Special Issue, we welcome original research or review articles on novel molecular biology methods and new techniques to verify the pathogenic mechanism of retinal disorders.

The relevant retinal diseases include age-related macular degeneration, diabetic retinopathy, central serous retinopathy, choroidal melanoma, retinoblastoma, retinal detachment, proliferative vitreoretinopathy, retinopathy of prematurity, posterior uveitis, inherited retinal diseases, macular hole, epiretinal membrane, and retinal vein occlusion.

Dr. Dimitra Skondra
Prof. Dr. Francine Behar-Cohen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • retina
  • nutrition
  • genetics
  • high-throughput RNA/DNA sequencing
  • stem cells
  • metabolomics
  • microbiome
  • transcriptomics
  • meta-transcriptomics
  • proteomics
  • epigenetics
  • single-cell
  • multi-omics
  • bioinformatics
  • network medicine
  • advanced retinal imaging
  • biotechnology
  • retina organoids
  • iPSC
  • network medicine
  • computational analysis

Related Special Issue

Published Papers (9 papers)

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Research

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15 pages, 3229 KiB  
Article
Silicone Oil-Induced Glaucomatous Neurodegeneration in Rhesus Macaques
by Ala Moshiri, Fang Fang, Pei Zhuang, Haoliang Huang, Xue Feng, Liang Li, Roopa Dalal and Yang Hu
Int. J. Mol. Sci. 2022, 23(24), 15896; https://doi.org/10.3390/ijms232415896 - 14 Dec 2022
Cited by 3 | Viewed by 1780
Abstract
Previously, we developed a simple procedure of intracameral injection of silicone oil (SO) into mouse eyes and established the mouse SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation and significant glaucomatous neurodegeneration. Because the anatomy of the non-human [...] Read more.
Previously, we developed a simple procedure of intracameral injection of silicone oil (SO) into mouse eyes and established the mouse SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation and significant glaucomatous neurodegeneration. Because the anatomy of the non-human primate (NHP) visual system closely resembles that of humans, it is the most likely to predict human responses to diseases and therapies. Here we tried to replicate the mouse SOHU glaucoma model in rhesus macaque monkeys. All six animals that we tested showed significant retinal ganglion cell (RGC) death, optic nerve (ON) degeneration, and visual functional deficits at both 3 and 6 months. In contrast to the mouse SOHU model, however, IOP changed dynamically in these animals, probably due to individual differences in ciliary body tolerance capability. Further optimization of this model is needed to achieve consistent IOP elevation without permanent damage of the ciliary body. The current form of the NHP SOHU model recapitulates the severe degeneration of acute human glaucoma, and is therefore suitable for assessing experimental therapies for neuroprotection and regeneration, and therefore for translating relevant findings into novel and effective treatments for patients with glaucoma and other neurodegenerations. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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14 pages, 1340 KiB  
Article
Proteomics of Aqueous Humor as a Source of Disease Biomarkers in Retinoblastoma
by Angela Galardi, Christina Stathopoulos, Marta Colletti, Chiara Lavarello, Ida Russo, Raffaele Cozza, Antonino Romanzo, Angel M. Carcaboso, Franco Locatelli, Andrea Petretto, Francis L. Munier and Angela Di Giannatale
Int. J. Mol. Sci. 2022, 23(21), 13458; https://doi.org/10.3390/ijms232113458 - 3 Nov 2022
Cited by 7 | Viewed by 1655
Abstract
Aqueous humor (AH) can be easily and safely used to evaluate disease-specific biomarkers in ocular disease. The aim of this study was to identify specific proteins biomarkers in the AH of retinoblastoma (RB) patients at various stages of the disease. We analyzed the [...] Read more.
Aqueous humor (AH) can be easily and safely used to evaluate disease-specific biomarkers in ocular disease. The aim of this study was to identify specific proteins biomarkers in the AH of retinoblastoma (RB) patients at various stages of the disease. We analyzed the proteome of 53 AH samples using high-resolution mass spectrometry. We grouped the samples according to active vitreous seeding (Group 1), active aqueous seeding (Group 2), naive RB (group 3), inactive RB (group 4), and congenital cataracts as the control (Group 5). We found a total of 889 proteins in all samples. Comparative parametric analyses among the different groups revealed three additional proteins expressed in the RB groups that were not expressed in the control group. These were histone H2B type 2-E (HISTH2B2E), InaD-like protein (PATJ), and ubiquitin conjugating enzyme E2 V1 (UBE2V1). Upon processing the data of our study with the OpenTarget Tool software, we found that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and CD44 were more highly expressed in the RB groups. Our results provide a proteome database regarding AH related to RB disease that may be used as a source of biomarkers. Further prospective studies should validate our finding in a large cohort of RB patients. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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15 pages, 1304 KiB  
Article
Using Computational Drug-Gene Analysis to Identify Novel Therapeutic Candidates for Retinal Neuroprotection
by Edward Xie, Urooba Nadeem, Bingqing Xie, Mark D’Souza, Dinanath Sulakhe and Dimitra Skondra
Int. J. Mol. Sci. 2022, 23(20), 12648; https://doi.org/10.3390/ijms232012648 - 21 Oct 2022
Cited by 3 | Viewed by 1571
Abstract
Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the [...] Read more.
Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the retina using a computational bioinformatics approach. We queried the National Center for Biotechnology Information (NCBI) to identify genes associated with retinal neuroprotection. Enrichment analysis was performed using ToppGene to identify compounds related to the identified genes. This analysis constructs a Pharmacome from multiple drug-gene interaction databases to predict compounds with statistically significant associations to genes involved in retinal neuroprotection. Compounds with known deleterious effects (e.g., asbestos, ethanol) or with no clinical indications (e.g., paraquat, ozone) were manually filtered. We identified numerous drug/chemical classes associated to multiple genes implicated in retinal neuroprotection using a systematic computational approach. Anti-diabetics, lipid-lowering medicines, and antioxidants are among the treatments anticipated by this analysis, and many of these drugs could be readily repurposed for retinal neuroprotection. Our technique serves as an unbiased tool that can be utilized in the future to lead focused preclinical and clinical investigations for complex processes such as neuroprotection, as well as a wide range of other ocular pathologies. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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14 pages, 2587 KiB  
Article
Absence of Gut Microbiota Is Associated with RPE/Choroid Transcriptomic Changes Related to Age-Related Macular Degeneration Pathobiology and Decreased Choroidal Neovascularization
by Jason Y. Zhang, Bingqing Xie, Hugo Barba, Urooba Nadeem, Asadolah Movahedan, Nini Deng, Melanie Spedale, Mark D’Souza, Wendy Luo, Vanessa Leone, Eugene B. Chang, Betty Theriault, Dinanath Sulakhe and Dimitra Skondra
Int. J. Mol. Sci. 2022, 23(17), 9676; https://doi.org/10.3390/ijms23179676 - 26 Aug 2022
Cited by 13 | Viewed by 2205
Abstract
Studies have begun to reveal significant connections between the gut microbiome and various retinal diseases, including age-related macular degeneration (AMD). As critical supporting tissues of the retina, the retinal pigment epithelium (RPE) and underlying choroid play a critical role in retinal homeostasis and [...] Read more.
Studies have begun to reveal significant connections between the gut microbiome and various retinal diseases, including age-related macular degeneration (AMD). As critical supporting tissues of the retina, the retinal pigment epithelium (RPE) and underlying choroid play a critical role in retinal homeostasis and degeneration. However, the relationship between the microbiome and RPE/choroid remains poorly understood, particularly in animal models of AMD. In order to better elucidate this role, we performed high-throughput RNA sequencing of RPE/choroid tissue in germ-free (GF) and specific pathogen-free (SPF) mice. Furthermore, utilizing a specialized laser-induced choroidal neovascularization (CNV) model that we developed, we compared CNV size and inflammatory response between GF and SPF mice. After correction of raw data, 660 differentially expressed genes (DEGs) were identified, including those involved in angiogenesis regulation, scavenger and cytokine receptor activity, and inflammatory response—all of which have been implicated in AMD pathogenesis. Among lasered mice, the GF group showed significantly decreased CNV lesion size and microglial infiltration around CNV compared to the SPF group. Together, these findings provide evidence for a potential gut–RPE/choroidal axis as well as a correlation with neovascular features of AMD. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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17 pages, 4516 KiB  
Article
RNA-Seq Provides Insights into VEGF-Induced Signaling in Human Retinal Microvascular Endothelial Cells: Implications in Retinopathy of Prematurity
by Aniket Ramshekar, Colin A. Bretz and M. Elizabeth Hartnett
Int. J. Mol. Sci. 2022, 23(13), 7354; https://doi.org/10.3390/ijms23137354 - 1 Jul 2022
Cited by 3 | Viewed by 2083
Abstract
The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects [...] Read more.
The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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Review

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19 pages, 345 KiB  
Review
Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration
by Raji Rajesh Lenin, Yi Hui Koh, Zheting Zhang, Yan Zhuang Yeo, Bhav Harshad Parikh, Ivan Seah, Wendy Wong and Xinyi Su
Int. J. Mol. Sci. 2023, 24(10), 8763; https://doi.org/10.3390/ijms24108763 - 15 May 2023
Cited by 3 | Viewed by 2283
Abstract
Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads [...] Read more.
Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
14 pages, 1141 KiB  
Review
Interleukin-6 and Macular Edema: A Review of Outcomes with Inhibition
by Janine Yunfan Yang, David Goldberg and Lucia Sobrin
Int. J. Mol. Sci. 2023, 24(5), 4676; https://doi.org/10.3390/ijms24054676 - 28 Feb 2023
Cited by 7 | Viewed by 2672
Abstract
This paper describes the current literature on the molecular pathophysiology of interleukin-6 (IL-6) in the genesis of macular edema and on the outcomes with IL-6 inhibitors in the treatment of non-infectious macular edema. The role of IL-6 in the development of macular edema [...] Read more.
This paper describes the current literature on the molecular pathophysiology of interleukin-6 (IL-6) in the genesis of macular edema and on the outcomes with IL-6 inhibitors in the treatment of non-infectious macular edema. The role of IL-6 in the development of macular edema has been well elucidated. IL-6 is produced by multiple cells of the innate immune system and leads to a higher likelihood of developing autoimmune inflammatory diseases, such as non-infectious uveitis, through a variety of mechanisms. These include increasing the helper T-cell population over the regulatory T-cell population and leading to the increased expression of inflammatory cytokines, such as tumor necrosis factor-alpha. In addition to being key in the generation of uveitis and subsequent macular edema through these inflammatory pathways, IL-6 also can lead to the development of macular edema through other pathways. IL-6 induces the production of vascular endothelial growth factor (VEGF) and facilitates vascular leakage by downregulating tight junction proteins in retinal endothelial cells. Clinically, the use of IL-6 inhibitors has been found to be efficacious primarily in the context of treatment-resistant non-infectious uveitis and secondary macular edema. IL-6 is a key cytokine in retinal inflammation and macular edema. It is thus not surprising that the use of IL-6 inhibitors in treatment-resistant macular edema in the setting of non-infectious uveitis has been well documented as an effective treatment option. The use of IL-6 inhibitors in macular edema secondary to non-uveitic processes has only begun to be explored. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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29 pages, 2024 KiB  
Review
Vitreous Substitutes from Bench to the Operating Room in a Translational Approach: Review and Future Endeavors in Vitreoretinal Surgery
by Filippo Confalonieri, Natasha Josifovska, Gerard Boix-Lemonche, Ingar Stene-Johansen, Ragnheidur Bragadottir, Xhevat Lumi and Goran Petrovski
Int. J. Mol. Sci. 2023, 24(4), 3342; https://doi.org/10.3390/ijms24043342 - 7 Feb 2023
Cited by 1 | Viewed by 3905
Abstract
Vitreous substitutes are indispensable tools in vitreoretinal surgery. The two crucial functions of these substitutes are their ability to displace intravitreal fluid from the retinal surface and to allow the retina to adhere to the retinal pigment epithelium. Today, vitreoretinal surgeons can choose [...] Read more.
Vitreous substitutes are indispensable tools in vitreoretinal surgery. The two crucial functions of these substitutes are their ability to displace intravitreal fluid from the retinal surface and to allow the retina to adhere to the retinal pigment epithelium. Today, vitreoretinal surgeons can choose among a plethora of vitreous tamponades, and the tamponade of choice might be difficult to determine in the ever-expanding range of possibilities for a favorable outcome. The currently available vitreous substitutes have disadvantages that need to be addressed to improve the surgical outcome achievable today. Herein, the fundamental physical and chemical proprieties of all vitreous substitutes are reported, and their use and clinical applications are described alongside some surgical techniques of intra-operative manipulation. The major upcoming developments in vitreous substitutes are extensively discussed, keeping a translational perspective throughout. Conclusions on future perspectives are derived through an in-depth analysis of what is lacking today in terms of desired outcomes and biomaterials technology. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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22 pages, 1102 KiB  
Review
The Role of Intravitreal Corticosteroids in the Treatment of DME: Predictive OCT Biomarkers
by Marion R. Munk, Gabor Mark Somfai, Marc D. de Smet, Guy Donati, Marcel N. Menke, Justus G. Garweg and Lala Ceklic
Int. J. Mol. Sci. 2022, 23(14), 7585; https://doi.org/10.3390/ijms23147585 - 8 Jul 2022
Cited by 20 | Viewed by 4316
Abstract
This work aims to summarize predictive biomarkers to guide treatment choice in DME. Intravitreal anti-VEGF is considered the gold standard treatment for centers involving DME, while intravitreal steroid treatment has been established as a second-line treatment in DME. However, more than 1/3 of [...] Read more.
This work aims to summarize predictive biomarkers to guide treatment choice in DME. Intravitreal anti-VEGF is considered the gold standard treatment for centers involving DME, while intravitreal steroid treatment has been established as a second-line treatment in DME. However, more than 1/3 of the patients do not adequately respond to anti-VEGF treatment despite up to 4-weekly injections. Not surprisingly, insufficient response to anti-VEGF therapy has been linked to low-normal VEGF levels in the serum and aqueous humor. These patients may well benefit from an early switch to intravitreal steroid treatment. In these patients, morphological biomarkers visible in OCT may predict treatment response and guide treatment decisions. Namely, the presence of a large amount of retinal and choroidal hyperreflective foci, disruption of the outer retinal layers and other signs of chronicity such as intraretinal cysts extending into the outer retina and a lower choroidal vascular index are all signs suggestive of a favorable treatment response of steroids compared to anti-VEGF. This paper summarizes predictive biomarkers in DME in order to assist individual treatment decisions in DME. These markers will help to identify DME patients who may benefit from primary dexamethasone treatment or an early switch. Full article
(This article belongs to the Special Issue Frontier Research on Retina)
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