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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360760

RESUMO

Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.


Assuntos
Glaucoma , Neuroproteção , Células Ganglionares da Retina , Animais , Transporte Axonal , Axônios/metabolismo , Axônios/patologia , Modelos Animais de Doenças , Glaucoma/metabolismo , Glaucoma/patologia , Glaucoma/terapia , Humanos , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
2.
Front Immunol ; 12: 701295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394095

RESUMO

The current pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already become a global threat to the human population. Infection with SARS-CoV-2 leads to a wide spectrum of clinical manifestations. Ocular abnormalities have been reported in association with COVID-19, but the nature of the impairments was not specified. Here, we report a case of a female patient diagnosed with glaucoma on re-hospitalization for ocular complications two months after being discharged from the hospital upon recovery from COVID-19. Meanwhile, the patient was found re-positive for SARS-CoV-2 in the upper respiratory tract. The infection was also diagnosed in the aqueous humor through immunostaining with antibodies against the N protein and S protein of SARS-CoV-2. Considering the eye is an immune-privileged site, we speculate that SARS-CoV-2 survived in the eye and resulted in the patient testing re-positive for SARS-CoV-2.


Assuntos
Humor Aquoso/virologia , COVID-19/patologia , Glaucoma/patologia , Reinfecção/patologia , Idoso , COVID-19/complicações , Olho/patologia , Olho/virologia , Feminino , Glaucoma/complicações , Humanos , SARS-CoV-2/isolamento & purificação
3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445531

RESUMO

Glaucoma is associated with increased intraocular pressure (IOP), causing the apoptosis of retinal ganglion cells (RGCs) and the loss of their axons leading to blindness. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in several neural injuries, including retinopathies. The aim of this study was to investigate the effects of PACAP1-38 eye drops in a model of glaucoma. IOP was elevated bilaterally by injections of microbeads to block the aqueous humor outflow. The control groups received the same volume of saline. Animals were treated with PACAP1-38 (1 µg/drop, 3 × 1 drop/day) or vehicle for 4 weeks starting one day after the injections. Retinal morphology by histology and optical coherence tomography, function by electroretinography, and IOP changes were analyzed. Animals were sacrificed 8 weeks after the injections. Microbeads injections induced a significant increase in the IOP, while PACAP1-38 treatment lowered it to normal levels (~10 mmHg). Significant retinal degeneration and functional impairment were observed in the microbead-injected group without PACAP1-38 treatment. In the microbeads + PACAP1-38 group, the retinal morphology and functionality were close to the normal values. In summary, our results show that PACAP1-38, given in form of eye drops, is neuroprotective in glaucoma, providing the basis for potential future therapeutic administration.


Assuntos
Modelos Animais de Doenças , Glaucoma/tratamento farmacológico , Microesferas , Fármacos Neuroprotetores/farmacologia , Soluções Oftálmicas/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Degeneração Retiniana/prevenção & controle , Animais , Glaucoma/etiologia , Glaucoma/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia
4.
Biomolecules ; 11(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34356611

RESUMO

Glaucoma is a group of irreversible blinding eye diseases characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Currently, there is no effective method to fundamentally resolve the issue of RGC degeneration. Recent advances have revealed that visual function recovery could be achieved with stem cell-based therapy by replacing damaged RGCs with cell transplantation, providing nutritional factors for damaged RGCs, and supplying healthy mitochondria and other cellular components to exert neuroprotective effects and mediate transdifferentiation of autologous retinal stem cells to accomplish endogenous regeneration of RGC. This article reviews the recent research progress in the above-mentioned fields, including the breakthroughs in the fields of in vivo transdifferentiation of retinal endogenous stem cells and reversal of the RGC aging phenotype, and discusses the obstacles in the clinical translation of the stem cell therapy.


Assuntos
Glaucoma , Regeneração , Células Ganglionares da Retina/fisiologia , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Glaucoma/metabolismo , Glaucoma/patologia , Glaucoma/terapia , Humanos , Células-Tronco/patologia
5.
Invest Ophthalmol Vis Sci ; 62(10): 17, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34406331

RESUMO

Purpose: The purpose of this study was to determine the effects of the Sigma-1R (σ-1r) on retinal ganglion cell (RGC) survival following optic nerve crush (ONC) and the signaling mechanism involved in the σ-1r protection. Methods: The overall strategy was to induce injury by ONC and mitigate RGC death by increasing σ-1r expression and/or activate σ-1r activity in σ-1r K/O mice and wild type (WT) mice. AAV2-σ-1r vector was used to increase σ-1r expression and σ-1r agonist used to activate the σ-1r and RGCs were counted. Immunohistochemical and Western blot analysis determined phosphorylated (p)-c-Jun, c-Jun, and Caspase-3. Pattern electroretinography (PERG) determined RGC activity. Results: RGC counts and function were similar in pentazocine-treated WT mice when compared to untreated mice and in WT mice when compared with σ-1r K/O mice. Pentazocine-induced effects and the effects of σ-1r K/O were only observable after ONC. ONC resulted in decreased RGC counts and activity in both WT and σ-1r K/O mice, with σ-1r K/O mice experiencing significant decreases compared with WT mice. The σ-1r transgenic expression resulted in increased RGC counts and activity following ONC. In WT mice, treatment with σ-1r agonist pentazocine resulted in increased RGC counts and increased activity when compared with untreated WT mice. There were time-dependent increases in c-jun, p-c-jun, and caspase-3 expression in ONC mice that were mitigated with pentazocine-treatment. Conclusions: These findings suggest that the apoptotic pathway is involved in RGC losses seen in an ONC model. The σ-1r offers neuroprotection, as activation and/or transgenic expression of σ-1r attenuated the apoptotic pathway and restored RGCs number and function following ONC.


Assuntos
Glaucoma/genética , Traumatismos do Nervo Óptico/genética , Receptores sigma/genética , Células Ganglionares da Retina/patologia , Animais , Apoptose , Modelos Animais de Doenças , Eletrorretinografia , Glaucoma/complicações , Glaucoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compressão Nervosa/métodos , Traumatismos do Nervo Óptico/etiologia , Traumatismos do Nervo Óptico/patologia , Receptores sigma/biossíntese , Células Ganglionares da Retina/metabolismo , Transdução de Sinais
6.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299278

RESUMO

During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-ß) 2 levels. In this study we tested the hypothesis if the presence or absence of decorin (DCN), a small leucine-rich proteoglycan and a natural inhibitor of several members of the TGF family, would affect the expression of the TGF-ßs and connective tissue growth factor (CTGF/CCN2) in human ONH astrocytes and murine ON astrocytes. We found that DCN is present in the mouse ON and is expressed by human ONH and murine ON astrocytes. DCN expression and synthesis was significantly reduced after 24 h treatment with 3 nM CTGF/CCN2, while treatment with 4 pM TGF-ß2 only reduced expression of DCN significantly. Conversely, DCN treatment significantly reduced the expression of TGF-ß1, TGF-ß2 and CTGF/CCN2 vis-a-vis untreated controls. Furthermore, DCN treatment significantly reduced expression of fibronectin (FN) and collagen IV (COL IV). Notably, combined treatment with DCN and triciribine, a small molecule inhibitor of protein kinase B (AKT), attenuated effects of DCN on CTGF/CCN2, TGF-ß1, and TGF-ß2 mRNA expression. We conclude (1) that DCN is an important regulator of TGF-ß and CTGF/CCN2 expression in astrocytes of the ON and ONH, (2) that DCN thereby regulates the expression of extracellular matrix (ECM) components and (3) that DCN executes its negative regulatory effects on TGF-ß and CTGF/CCN2 via the pAKT/AKT signaling pathway in ON astrocytes.


Assuntos
Astrócitos/metabolismo , Decorina/farmacologia , Proteínas da Matriz Extracelular/metabolismo , Glaucoma/patologia , Proteína Oncogênica v-akt/metabolismo , Nervo Óptico/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glaucoma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nervo Óptico/efeitos dos fármacos , Transdução de Sinais
7.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201109

RESUMO

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFß2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFß2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFß2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.


Assuntos
Regulação da Expressão Gênica , Glaucoma/genética , MicroRNAs/genética , Disco Óptico/metabolismo , Doenças do Nervo Óptico/genética , Fator de Crescimento Transformador beta2/farmacologia , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Humanos , Disco Óptico/efeitos dos fármacos , Disco Óptico/patologia , Doenças do Nervo Óptico/tratamento farmacológico , Doenças do Nervo Óptico/patologia
8.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299211

RESUMO

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABAA receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions.


Assuntos
Neurônios GABAérgicos/metabolismo , Glaucoma/patologia , Células Ganglionares da Retina/patologia , Ácido gama-Aminobutírico/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Feminino , Neurônios GABAérgicos/patologia , Regulação da Expressão Gênica , Glaucoma/etiologia , Glaucoma/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Ganglionares da Retina/metabolismo
9.
Invest Ophthalmol Vis Sci ; 62(9): 35, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34297802

RESUMO

Purpose: We examined structural and functional changes in the outer retina of a mouse model of glaucoma. We examined whether these changes are a secondary consequence of damage in the inner retina and whether neuroprotection of the inner retina also prevents outer retinal changes. Methods: We used an established microbead occlusion model of glaucoma whereby intraocular pressure (IOP) was elevated. Specific antibodies were used to label rod and cone bipolar cells (BCs), horizontal cells (HCs), and retinal ganglion cells (RGCs), as well as synaptic components in control and glaucomatous eyes, to assess structural damage and cell loss. ERG recordings were made to assess outer retina function. Results: We found structural and functional damage of BCs, including significant cell loss and dendritic/axonal remodeling of HCs, following IOP elevation. The first significant loss of both BCs occurred at 4 to 5 weeks after microbead injection. However, early changes in the dendritic structure of RGCs were observed at 3 weeks, but significant changes in the rod BC axon terminal structure were not seen until 4 weeks. We found that protection of inner retinal neurons in glaucomatous eyes by pharmacological blockade of gap junctions or genetic ablation of connexin 36 largely prevented outer retinal damage. Conclusions: Together, our results indicate that outer retinal impairments in glaucoma are a secondary sequalae of primary damage in the inner retina. The finding that neuroprotection of the inner retina can also prevent outer retinal damage has important implications with regard to the targets for effective neuroprotective therapy.


Assuntos
Glaucoma/prevenção & controle , Pressão Intraocular/fisiologia , Ácido Meclofenâmico/administração & dosagem , Neuroproteção/fisiologia , Segmento Interno das Células Fotorreceptoras da Retina/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Modelos Animais de Doenças , Eletrorretinografia , Glaucoma/patologia , Glaucoma/fisiopatologia , Imuno-Histoquímica , Injeções , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Segmento Interno das Células Fotorreceptoras da Retina/metabolismo , Segmento Interno das Células Fotorreceptoras da Retina/ultraestrutura
10.
Exp Cell Res ; 406(1): 112737, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34324864

RESUMO

The retina is the innermost part of the eye of most vertebrates and it is essential for vision. The development, maintenance, and function of this laminated structure is tightly regulated by numerous genes. Deficiencies in the expression of these genes as well as deregulation of various molecular mechanisms can cause retinopathies and blindness. MicroRNAs (miRNAs) are one of the most important and effective molecular regulatory mechanisms that underlie the biology of the retina. miRNAs have specific functional roles in the development and maintenance of different retinal layers and retinal cell types. While previous studies have reported a large number of miRNAs linked to development, maintenance and diseases of the retina, no comprehensive study has properly discussed and integrated data from these studies. Given the particular importance of miR-204 in retinal biology, we intend to critically discuss the expression and functional significance of this miRNA in the development, maintenance, and pathologies of the retina. Moreover, we explore biological processes through which miR-204 influences retinal pathophysiology. This review highlights the crucial functions of miR-204 in the retina and suggests the putative mechanism of miR-204 action in retinal biology.


Assuntos
Retinopatia Diabética/genética , Glaucoma/genética , Degeneração Macular/genética , MicroRNAs/genética , Traumatismos do Nervo Óptico/genética , Retinoblastoma/genética , Animais , Sequência de Bases , Sequência Conservada , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Proteína 1 Homóloga a Discs-Large/genética , Proteína 1 Homóloga a Discs-Large/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glaucoma/metabolismo , Glaucoma/patologia , Humanos , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Retina/metabolismo , Retina/patologia , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Transdução de Sinais
11.
Am J Hum Genet ; 108(7): 1204-1216, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34077762

RESUMO

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.


Assuntos
Inteligência Artificial , Glaucoma/genética , Disco Óptico/diagnóstico por imagem , Adulto , Idoso , Algoritmos , Feminino , Estudo de Associação Genômica Ampla , Glaucoma/diagnóstico , Glaucoma/patologia , Humanos , Processamento de Imagem Assistida por Computador , Padrões de Herança , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Rede Nervosa , Disco Óptico/patologia , Fotografação , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073191

RESUMO

Despite being one of the most studied eye diseases, clinical translation of glaucoma research is hampered, at least in part, by the lack of validated preclinical models and readouts. The most popular experimental glaucoma model is the murine microbead occlusion model, yet the observed mild phenotype, mixed success rate, and weak reproducibility urge for an expansion of available readout tools. For this purpose, we evaluated various measures that reflect early onset glaucomatous changes in the murine microbead occlusion model. Anterior chamber depth measurements and scotopic threshold response recordings were identified as an outstanding set of tools to assess the model's success rate and to chart glaucomatous damage (or neuroprotection in future studies), respectively. Both are easy-to-measure, in vivo tools with a fast acquisition time and high translatability to the clinic and can be used, whenever judged beneficial, in combination with the more conventional measures in present-day glaucoma research (i.e., intraocular pressure measurements and post-mortem histological analyses). Furthermore, we highlighted the use of dendritic arbor analysis as an alternative histological readout for retinal ganglion cell density counts.


Assuntos
Glaucoma , Microesferas , Células Ganglionares da Retina , Animais , Modelos Animais de Doenças , Feminino , Glaucoma/induzido quimicamente , Glaucoma/metabolismo , Glaucoma/patologia , Masculino , Camundongos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
13.
PLoS One ; 16(5): e0251249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33956906

RESUMO

PURPOSE: To investigate the reproducibility for the iridocorneal angle evaluations using the pictures obtained by a gonioscopic camera, Gonioscope GS-1 (Nidek Co., Gamagori, Japan). METHODS: The pragmatic within-patient comparative diagnostic evaluations for 140 GS-1 gonio-images obtained from 35 eyes of 35 patients at four ocular sectors (superior, temporal, inferior, and nasal angles) were conducted by five independent ophthalmologists including three glaucoma specialists in a masked fashion twice, 1 week apart. We undertook the observer agreement and correlation analyses of Scheie's angle width and pigmentation gradings and detection of peripheral anterior synechia and Sampaolesi line. RESULTS: The respective Fleiss' kappa values for the four elements between manual gonioscopy and automated gonioscope by the glaucoma specialist were 0.22, 0.40, 0.32 and 0.58. Additionally, the respective intraobserver agreements for the four elements by the glaucoma specialist each were 0.32 to 0.65, 0.24 to 0.71, 0.35 to 0.70, and 0.20 to 0.76; the Fleiss' kappa coefficients for the four elements among the three glaucoma specialists were, respectively, 0.31, 0.38, 0.31, and 0.17; the Fleiss' kappa coefficients for the angle width and pigmentation gradings between the two glaucoma specialists each were 0.30 to 0.35, and 0.29 to 0.43, respectively. Overall, the Kendall's tau coefficients for the angle gradings reflected the positive correlations in the evaluations. CONCLUSION: Our findings suggested slight-to-substantial intraobserver agreement and slight-to-fair (among the three) or fair-to-moderate (between the two each) interobserver agreement for the angle assessments using GS-1 gonio-photos even by glaucoma specialists. Sufficient training and a solid consensus should allow us to perform more reliable angle assessments using gonio-photos with high reproducibility.


Assuntos
Câmara Anterior/patologia , Gonioscopia/métodos , Variações Dependentes do Observador , Adulto , Idoso , Idoso de 80 Anos ou mais , Automação , Feminino , Glaucoma/diagnóstico , Glaucoma/patologia , Gonioscopia/normas , Gonioscopia/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
14.
PLoS Genet ; 17(5): e1009497, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979322

RESUMO

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.


Assuntos
Bancos de Espécimes Biológicos , Variação Genética , Fenótipo , Retina/metabolismo , Tomografia de Coerência Óptica , Feminino , Genótipo , Glaucoma/genética , Glaucoma/patologia , Cor de Cabelo/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Controle de Qualidade , Retina/patologia , Reino Unido , Transtornos da Visão , Acuidade Visual/genética
15.
Theranostics ; 11(13): 6154-6172, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995651

RESUMO

SH2 domain containing tyrosine phosphatase 2 (Shp2; PTPN11) regulates several intracellular pathways downstream of multiple growth factor receptors. Our studies implicate that Shp2 interacts with Caveolin-1 (Cav-1) protein in retinal ganglion cells (RGCs) and negatively regulates BDNF/TrkB signaling. This study aimed to investigate the mechanisms underlying the protective effects of shp2 silencing in the RGCs in glaucomatous conditions. Methods: Shp2 was silenced in the Cav-1 deficient mice and the age matched wildtype littermates using adeno-associated viral (AAV) constructs. Shp2 expression modulation was performed in an acute and a chronic mouse model of experimental glaucoma. AAV2 expressing Shp2 eGFP-shRNA under a strong synthetic CAG promoter was administered intravitreally in the animals' eyes. The contralateral eye received AAV-eGFP-scramble-shRNA as control. Animals with Shp2 downregulation were subjected to either microbead injections or acute ocular hypertension experimental paradigm. Changes in inner retinal function were evaluated by measuring positive scotopic threshold response (pSTR) while structural and biochemical alterations were evaluated through H&E staining, western blotting and immunohistochemical analysis of the retinal tissues. Results: A greater loss of pSTR amplitudes was observed in the WT mice compared to Cav-1-/- retinas in both the models. Silencing of Shp2 phosphatase imparted protection against inner retinal function loss in chronic glaucoma model in WT mice. The functional rescue also translated to structural preservation of ganglion cell layer in the chronic glaucoma condition in WT mice which was not evident in Cav-1-/- mice retinas. Conclusions: This study indicates that protective effects of Shp2 ablation under chronic experimental glaucoma conditions are dependent on Cav-1 in the retina, suggesting in vivo interactions between the two proteins.


Assuntos
Caveolina 1/fisiologia , Terapia Genética , Vetores Genéticos/uso terapêutico , Glaucoma/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Retina/patologia , alfa-Globulinas/genética , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Caveolina 1/deficiência , Caveolina 1/genética , DNA Complementar/genética , Dependovirus/genética , Quinase 1 de Adesão Focal/fisiologia , Técnicas de Silenciamento de Genes , Genes Reporter , Genes Sintéticos , Glaucoma/metabolismo , Glaucoma/patologia , Integrina beta1/fisiologia , Pressão Intraocular , Injeções Intravítreas , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 11/biossíntese , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Tirosina Quinases/fisiologia , Regulação para Cima
16.
Genes (Basel) ; 12(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799827

RESUMO

Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers three independent characteristics for the expression of each gene: level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate (DiI). We observed a higher relative expression variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted protein-protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pairwise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual gene expression and disclosed changes in the control of expression of complement cascade and Notch signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.


Assuntos
Glaucoma , Traumatismos do Nervo Óptico , Nervo Óptico , Células Ganglionares da Retina , Transcriptoma , Animais , Feminino , Glaucoma/genética , Glaucoma/metabolismo , Glaucoma/patologia , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Ratos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
17.
J Mater Chem B ; 9(15): 3335-3345, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881417

RESUMO

The elevation of intraocular pressure (IOP) is an important risk factor in the development of primary open angle glaucoma (POAG), which is the main cause of irreversible vision loss. miRNAs are promising new anti-glaucoma therapeutic agents. However, the low stability and cellular transfection of miRNA in vivo hinder its further application. This study aims to investigate the use of polydopamine-polyethylenimine nanoparticles (PDA/PEI NPs) as miRNA carriers in the treatment of ocular hypertension and glaucoma. The in vitro study proves that the carrier preserves the activity of nucleic acid for a long period. Besides, it has comparable transfection efficiency with commercially available vehicles, while having lower cytotoxicity. It has been demonstrated in the animal model that PDA/PEI NPs successfully reach the target tissues without an obvious inflammatory response. PDA/PEI NPs/miR-21-5p increases the permeability of porcine angular aqueous plexus cells, thereby reducing IOP by facilitating the conventional outflow pathway at least partially through the pathway involving endothelial nitric oxide synthase. Our results indicate that PDA/PEI NPs/miR-21-5p is a promising anti-glaucoma drug for treating POAG. And the delivery strategy may be extended to other gene therapy in treating intraocular diseases.


Assuntos
Sistemas de Liberação de Medicamentos , Glaucoma/terapia , Indóis/química , Pressão Intraocular , MicroRNAs/metabolismo , Nanopartículas/química , Polímeros/química , Animais , Sobrevivência Celular , Portadores de Fármacos/química , Glaucoma/metabolismo , Glaucoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Estrutura Molecular , Polietilenoimina/química
18.
Exp Eye Res ; 207: 108571, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33844961

RESUMO

Glaucoma is a collection of diseases that lead to an irreversible vision loss due to damage of retinal ganglion cells (RGCs). Although the underlying events leading to RGC death are not fully understood, recent research efforts are beginning to define the genetic changes that play a critical role in the initiation and progression of glaucomatous injury and RGC death. Several genetic and experimental animal models have been developed to mimic glaucomatous neurodegeneration. These models differ in many respects but all result in the loss of RGCs. Assessing transcriptional changes across different models could provide a more complete perspective on the molecular drivers of RGC degeneration. For the past several decades, changes in the retinal transcriptome during neurodegeneration process were defined using microarray methods, RNA sequencing and now single cell RNA sequencing. It is understood that these methods have strengths and weaknesses due to technical differences and variations in the analytical tools used. In this review, we focus on the use of transcriptome-wide expression profiling of the changes occurring as RGCs are lost across different glaucoma models. Commonalities of optic nerve crush and glaucoma-induced neurodegeneration are identified and discussed.


Assuntos
Modelos Animais de Doenças , Glaucoma/patologia , Degeneração Neural/patologia , Traumatismos do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Transcriptoma/genética , Animais , Proteínas do Olho/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Glaucoma/genética , Camundongos , Traumatismos do Nervo Óptico/genética , Análise de Sequência de RNA , Transdução de Sinais/fisiologia , Regulação para Cima
19.
Sci Rep ; 11(1): 9052, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907301

RESUMO

Recently, we established silicone oil-induced ocular hypertension (SOHU) mouse model with significant glaucomatous neurodegeneration. Here we characterize two additional variations of this model that simulate two distinct glaucoma types. The first is a chronic model produced by high frequency (HF) pupillary dilation after SO-induced pupillary block, which shows sustained moderate IOP elevation and corresponding slow, mild glaucomatous neurodegeneration. We also demonstrate that although SO removal quickly returns IOP to normal, the glaucomatous neurodegeneration continues to advance to a similar degree as in the HF group without SO removal. The second, an acute model created by no pupillary dilation (ND), shows a greatly elevated IOP and severe inner retina degeneration at an early time point. Therefore, by a straightforward dilation scheme, we extend our original SOHU model to recapitulate phenotypes of two major glaucoma forms, which will be invaluable for selecting neuroprotectants and elucidating their molecular mechanisms.


Assuntos
Modelos Animais de Doenças , Glaucoma/patologia , Hipertensão Ocular/fisiopatologia , Degeneração Retiniana/patologia , Células Ganglionares da Retina/patologia , Óleos de Silicone/toxicidade , Doença Aguda , Animais , Feminino , Glaucoma/induzido quimicamente , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipertensão Ocular/induzido quimicamente , Degeneração Retiniana/induzido quimicamente , Células Ganglionares da Retina/efeitos dos fármacos , Óleos de Silicone/administração & dosagem
20.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925119

RESUMO

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.


Assuntos
Glaucoma/metabolismo , Insulina/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Modelos Animais de Doenças , Glaucoma/patologia , Glaucoma/terapia , Humanos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Neuroproteção , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transdução de Sinais
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