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1.
Nihon Yakurigaku Zasshi ; 155(2): 81-86, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115483

RESUMO

Because visual information accounts for 80-90% of sensory information that we get from our circumstance, loss of vision seriously diminishes our quality of life. According to a recent epidemiological study, glaucoma is the first, and retinitis pigmentosa (RP) is the second leading causes of acquired blindness in Japan. Degeneration of the retinal ganglion cells (RGC) and photoreceptor cells causes glaucoma and RP, respectively. Intraocular pressure-lowering therapy is an only effective treatment for glaucoma, and the agents that protect RGC directly against glaucomatous injury have not been available yet. In addition, there is no effective treatment for RP at present. microRNAs are a class of small, endogenous, non-coding RNAs comprised of approximately 20 nucleotides. It has been clarified that microRNAs reduces the stability of the target mRNAs and/or repress the translation of the target genes. A single microRNA can affect the transcription of multiple mRNAs, and almost 30% of human genes are thought to be regulated by microRNAs. Therefore, it has been considered that the expression changes of microRNAs are possible to cause various diseases, such as cancer and neurodegenerative diseases. Recently, the expression changes in microRNAs have been reported in the retina of experimental model animals for glaucoma and RP. The expressional changes of microRNAs are suggested to be related with development and progression of glaucoma and RP. Here, we will discuss about the relationship between the expressional changes of microRNAs and neuronal cell death in glaucoma and RP.


Assuntos
MicroRNAs/genética , Retina/patologia , Degeneração Retiniana/genética , Animais , Modelos Animais de Doenças , Glaucoma/genética , Glaucoma/patologia , Humanos , Degeneração Retiniana/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia
2.
Invest Ophthalmol Vis Sci ; 61(2): 43, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32106290

RESUMO

Purpose: Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness worldwide in the working-age population, and the incidence is rising. Until now it has been difficult to define initiating events and disease progression at the molecular level, as available diabetic rodent models do not present the full spectrum of neural and vascular pathologies. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 were previously shown to display a diabetic phenotype from larval stages through adulthood. In this study, pdx1 mutants were examined for retinal vascular and neuronal pathology to demonstrate suitability of these fish for modeling DR. Methods: Vessel morphology was examined in pdx1 mutant and control fish expressing the fli1a:EGFP transgene. We further characterized vascular and retinal phenotypes in mutants and controls using immunohistochemistry, histology, and electron microscopy. Retinal function was assessed using electroretinography. Results: Pdx1 mutants exhibit clear vascular phenotypes at 2 months of age, and disease progression, including arterial vasculopenia, capillary tortuosity, and hypersprouting, could be detected at stages extending over more than 1 year. Neural-retinal pathologies are consistent with photoreceptor dysfunction and loss, but do not progress to blindness. Conclusions: This study highlights pdx1 mutant zebrafish as a valuable complement to rodent and other mammalian models of DR, in particular for research into the mechanistic interplay of diabetes with vascular and neuroretinal disease. They are furthermore suited for molecular studies to identify new targets for treatment of early as well as late DR.


Assuntos
Retinopatia Diabética/patologia , Células Fotorreceptoras/patologia , Degeneração Retiniana/patologia , Vasos Retinianos/patologia , Análise de Variância , Animais , Diabetes Mellitus Experimental , Retinopatia Diabética/fisiopatologia , Eletrorretinografia , Degeneração Retiniana/fisiopatologia , Vasos Retinianos/fisiopatologia , Peixe-Zebra
3.
Zhonghua Yan Ke Za Zhi ; 56(2): 149-154, 2020 Feb 11.
Artigo em Chinês | MEDLINE | ID: mdl-32074826

RESUMO

The outer retinal tubular structure (ORT) indicates a round or oval-shaped structure with a highly reflective border and a relatively low reflective lumen on spectrum-domain coherence tomography. ORTs are located in the outer nuclear layer accompanied by disruption and curling of the external limiting membrane and retinal pigment epithelial atrophy. Histopathological researches have revealed that ORTs are some kind of remodeling of the outer retina especially photoreceptors under pathological conditions, representing an advanced damage to the outer retina and a common final pathway of various retinal degenerative diseases. ORTs are common in neovascular age-related macular degeneration. They show some similarities in morphology with inter retinal fluid or cystoid edema on spectrum-domain coherence tomography, but they are not an indication for neovascular activity and retreatment. Their response to anti-vascular endothelial growth factor is poor, and the visual prognosis is not optimistic. Therefore, raising awareness of ORTs is very important for guiding clinical treatment and judging prognosis. (Chin J Ophthalmol, 2020, 56: 149-154).


Assuntos
Degeneração Retiniana , Tomografia de Coerência Óptica , Humanos , Células Fotorreceptoras de Vertebrados , Degeneração Retiniana/diagnóstico por imagem , Degeneração Retiniana/patologia , Estudos Retrospectivos
4.
Invest Ophthalmol Vis Sci ; 60(15): 5124-5135, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31834350

RESUMO

Purpose: Mutations in CACNA2D4, encoding the α2δ4 subunit of retinal voltage-gated calcium channels (Cav), cause a rare type of retinal dysfunction in human, mainly affecting cone vision. Here, we investigate the role of CACNA2D4 in targeting of Cav, its influence on cone-mediated signal transmission, and the cellular and subcellular changes upon loss of α2δ4 by exploiting the advantages of the cone-dominant zebrafish as model system. Methods: We identified two zebrafish CACNA2D4 paralogs (cacna2d4a and cacna2d4b), analyzed their expression by RNA in situ hybridization and introduced truncating frameshift mutations through CRISPR/Cas9-mediated mutagenesis. We analyzed retinal function and morphology of the single and double mutant lines by electroretinography, immunohistochemistry, light- and electron microscopy. Results: Knockout of cacna2d4b reduces the expression of Cacna1fa, the pore-forming subunit of retinal Cav1.4, whereas loss of cacna2d4a did not. Only knockout of both paralogs impaired cone-mediated ERG b-wave amplitude. The number of "floating" ribbons is increased in double-KO, while retinal morphology and expression of postsynaptic mGluR6b remain largely unaffected. Both Cacna1fa and Ribeyeb show ectopic punctate expression in cacna2d4b-KO and double-KO photoreceptors. Conclusions: We find that increasing the expression of Cav at the synaptic membrane is an evolutionarily conserved function of Cacna2d4b. Yet, since both paralogs participate in cone synaptic transmission, we propose partial subfunctionalization in zebrafish. Similar to human patients, our double KO zebrafish model shows mild cone dysfunction, which was not associated with signs of retinal degeneration. Therefore, cacna2d4-KO zebrafish is a suitable model to study the pathophysiological mechanisms underlying CACNA2D4 dysfunction in human.


Assuntos
Canais de Cálcio Tipo L/genética , DNA/genética , Regulação da Expressão Gênica , Degeneração Retiniana/genética , Animais , Canais de Cálcio Tipo L/biossíntese , DNA/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Imuno-Histoquímica , Células Fotorreceptoras Retinianas Cones/patologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Transmissão Sináptica , Peixe-Zebra
5.
Adv Exp Med Biol ; 1185: 175-179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884608

RESUMO

We present evidence that protein citrullination, a proinflammatory and immune system-activating posttranslational modification (PTM) of arginine residues mediated by peptidyl arginine deiminases (PADs), is elevated in mouse models of retinal degenerations. Together with the fact that the animal models that we investigated (and their human counterparts) exhibit also anti-retinal autoantibodies, we propose that retinal citrullination is an immunogenic trigger that activates the immune system both locally and systemically, contributing to disease pathogenesis. Consistent with this possibility, we show that PAD compromise reduces the severity of Mertk-related retinal degeneration. Thus, PAD inhibition may be as a potential treatment strategy for retinal degenerations.


Assuntos
Autoimunidade , Citrulinação , Sistema Imunitário , Inflamação/patologia , Desiminases de Arginina em Proteínas/fisiologia , Degeneração Retiniana/patologia , Animais , Citrulina , Humanos , Camundongos
6.
Adv Exp Med Biol ; 1185: 181-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884609

RESUMO

As the resident macrophages of central nervous system, microglia reside in the plexiform and nerve fiber layers of the retina. In degenerative diseases, monocyte-derived macrophages can be recruited to the retina, and histopathology shows abnormal accumulation of macrophages subretinally. However, due to lack of known markers, recruited cells and resident microglia are phenotypically indistinguishable, leaving a major knowledge gap about their potentially independent roles. Here, we used single cell RNA-seq and analyzed over 10,000 immune cells of mouse retinas from normal control and light damage-induced retinal degeneration. We observed ten major macrophage clusters. Moreover, combining trajectory analysis and in situ validation allowed us to pinpoint that subretinal phagocytes are microglia-derived and express high levels of Gal3, Cd68, and Lpl but not P2ry12. Hence, we have identified novel subretinal macrophage markers indicative of their origin and phenotype, which may be useful in other degeneration models and human specimens.


Assuntos
Microglia/classificação , Degeneração Retiniana/patologia , Animais , Modelos Animais de Doenças , Humanos , Macrófagos/classificação , Macrófagos/citologia , Camundongos , Microglia/citologia , RNA-Seq , Retina/citologia
7.
Adv Exp Med Biol ; 1185: 295-299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884627

RESUMO

The degeneration of photoreceptors is a common hallmark of ocular diseases like retinitis pigmentosa (RP) or age-related macular degeneration (AMD). To experimentally induce photoreceptor degeneration, the light damage paradigm is frequently used. In this study we show that the exposure to high amounts of cool white light (10,000 lux, 1 h) resulted in a more than 11-fold higher apoptotic rate in the retina compared to light exposure with 5000 lux for 30 min. Consequently, exposure to intense light resulted in a significant downregulation of retinal mRNA expression levels of the reference genes Gapdh, Gnb2l, Rpl32, Rps9, Actb, Ubc or Tbp compared to untreated controls. Investigators performing light-induced photoreceptor degeneration should be aware of the fact that higher light intensities will result in a dysregulation of reference genes.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Luz , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Retina/efeitos da radiação , Apoptose , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Células Fotorreceptoras de Vertebrados/patologia , Retina/citologia , Degeneração Retiniana/patologia , Retinite Pigmentosa/patologia
8.
Adv Exp Med Biol ; 1185: 301-304, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884628

RESUMO

Inherited retinal degenerations (IRDs) are a genetically heterogeneous group of disorders characterized by the progressive loss of photoreceptor cells. Despite this heterogeneity in the disease-causing mutation, common underlying mechanisms promoting photoreceptor cell death may be present. Dysregulation of photoreceptor cyclic nucleotide signaling may be one such common feature differentiating healthy from diseased photoreceptors. Here we review evidence that elevated retinal cAMP levels promote photoreceptor death and are a common feature of numerous animal models of IRDs. Improving our understanding of how cAMP levels become elevated and identifying downstream effectors may prove important for the development of therapeutics that will be applicable to multiple forms of the disease.


Assuntos
Morte Celular , AMP Cíclico/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/patologia , Animais , Modelos Animais de Doenças , Retina/metabolismo , Transdução de Sinais
9.
Adv Exp Med Biol ; 1185: 353-358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884637

RESUMO

Neurotrophic factors can promote the survival of degenerating retinal cells through the activation of STAT3 pathway. Thus, augmenting STAT3 activation in the retina has been proposed as potential therapy for retinal dystrophies. On the other hand, aberrant activation of STAT3 pathway is oncogenic and implicated in diverse human diseases. Furthermore, the STAT3/SOCS3 axis has been shown to induce the degradation of rhodopsin during retinal inflammation. In this study, we generated and used mice with constitutive activation of STAT3 pathway in the retina to evaluate the safety and consequences of enhancing STAT3 activities in the retina as a potential treatment for retinal degenerative diseases. We show that long-term activation of the STAT3 pathway can induce retinal degenerative changes and also exacerbate uveitis and other intraocular inflammatory diseases. Mechanisms underlying the development of vision impairment in the STAT3c-Tg mice derived in part from STAT3-mediated inhibition of rhodopsin and overexpression of SOCS3 in the retina. These results suggest that much caution should be exercised in the use of STAT3 augmentation therapy for retinal dystrophies.


Assuntos
Envelhecimento , Retina/patologia , Degeneração Retiniana/patologia , Fator de Transcrição STAT3/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina , Uveíte/patologia
10.
Adv Exp Med Biol ; 1185: 431-436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884650

RESUMO

Extracellular vesicles (EVs) are membranous structures released by cells, including those of the retinal pigment epithelium (RPE) and photoreceptors. The cargo of EVs includes genetic material and proteins, making these vesicles essential in cell communication. Among the genetic materials, we find a large number of microRNAs (miRNAs), small chains of noncoding RNA. In the case of EVs from the retina, changes have also been observed in the number and cargo of EVs.Our group confirmed that damaged RPE cells in vitro release a greater number of EVs with a higher pro-angiogenic factor (VEGFR-1 and VEGFR-2) than control non-damaged cells, thus increasing neovascularization in endothelial cell cultures. This indicates that something similar could happen in patients suffering from some types of retinal degeneration that occur with angiogenesis, such as wet AMD or RD.Here, we investigated the role of EVs in photoreceptor degeneration, and we report for the first time on CD9 and CD81, closely related tetraspanins, in wild-type and rd1 retinae. Our study demonstrates the involvement of EVs in the process of inherited photoreceptor degeneration in a PDE6 mutation.


Assuntos
Vesículas Extracelulares , Degeneração Retiniana/patologia , Retinite Pigmentosa/patologia , Tetraspanina 28/metabolismo , Tetraspanina 29/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Humanos , Retina , Epitélio Pigmentado da Retina/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Adv Exp Med Biol ; 1185: 169-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884607

RESUMO

Although the retina resides within the immune-protected ocular environment, inflammatory processes mounted in the eye can lead to retinal damage. Unchecked chronic ocular inflammation leads to retinal damage. Thus, retinal degenerative diseases that result in chronic inflammation accelerate retinal tissue destruction and vision loss. Treatments for chronic retinal inflammation involve corticosteroid administration, which has been associated with glaucoma and cataract formation. Therefore, we must consider novel, alternative treatments. Here, we provide a brief review of our current understanding of chronic innate inflammatory processes in retinal degeneration and the complex role of a putative inflammatory regulator, Caveolin-1 (Cav1). Furthermore, we suggest that the complex role of Cav1 in retinal inflammatory modulation is likely dictated by cell type-specific subcellular localization.


Assuntos
Caveolina 1/metabolismo , Inflamação/patologia , Retina/patologia , Humanos , Degeneração Retiniana/patologia
12.
Ophthalmic Surg Lasers Imaging Retina ; 50(10): 620-626, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31671194

RESUMO

BACKGROUND AND OBJECTIVE: To identify choroidal neovascular membrane (CNVM) associated with spectral-domain optical coherence tomography (SD-OCT)-defined pigment epithelial detachment (PED) using SD-OCT angiography (SD-OCTA). PATIENTS AND METHODS: Sixty-nine patients with same-day OCT and OCTA imaging were reviewed, and 41 eyes of 29 patients with PEDs were included. OCTs were analyzed for PED type, fluid, and subretinal hyperreflective material (SHRM). RESULTS: Twenty-seven eyes (66%) demonstrated CNVM on OCTA beneath all subtypes of PED. Twenty-two eyes (75.9%) with fluid or SHRM demonstrated CNVM on OCTA (P = .036). Fluid corresponded in a statistically significant manner with treatment (P = .0032), whereas SHRM did not (P = .613). OCTA-defined CNVM showed borderline statistically significant correlation to treatment (P = .05). Increased choroidal flow signal seen in 50% of eyes did not demonstrate statistically significant correlation to the presence of fluid on SD-OCT (P = .2798) or treatment decision (P = .678). A subset of 14 untreated eyes with CNVM was analyzed, 21% of which required treatment at subsequent visits. CONCLUSIONS: OCTA-defined CNVM was seen in all subtypes of PED in clinically active and inactive disease. The role of OCTA in predicting need for treatment remains to be established. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:620-626.].


Assuntos
Neovascularização de Coroide/patologia , Degeneração Retiniana/patologia , Descolamento Retiniano/patologia , Epitélio Pigmentado da Retina/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/diagnóstico por imagem , Feminino , Angiofluoresceinografia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos
13.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590277

RESUMO

The retina is the light sensitive part of the eye and nervous tissue that have been used extensively to characterize the function of the central nervous system. The retina has a central position both in fundamental biology and in the physiopathology of neurodegenerative diseases. We address the contribution of functional genomics to the understanding of retinal biology by reviewing key events in their historical perspective as an introduction to major findings that were obtained through the study of the retina using genomics, transcriptomics and proteomics. We illustrate our purpose by showing that most of the genes of interest for retinal development and those involved in inherited retinal degenerations have a restricted expression to the retina and most particularly to photoreceptors cells. We show that the exponential growth of data generated by functional genomics is a future challenge not only in terms of storage but also in terms of accessibility to the scientific community of retinal biologists in the future. Finally, we emphasize on novel perspectives that emerge from the development of redox-proteomics, the new frontier in retinal biology.


Assuntos
Células Fotorreceptoras/metabolismo , Proteoma , Degeneração Retiniana/genética , Transcriptoma , Animais , Genômica/métodos , Humanos , Células Fotorreceptoras/patologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia
14.
Adv Exp Med Biol ; 1186: 1-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31654384

RESUMO

Pluripotent stem cell technology, including human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), has provided a suitable platform to investigate molecular and pathological alterations in an individual cell type using patient's own cells. Importantly, hiPSCs/hESCs are amenable to genome editing providing unique access to isogenic controls. Specifically, the ability to introduce disease-causing mutations in control (unaffected) and conversely correct disease-causing mutations in patient-derived hiPSCs has provided a powerful approach to clearly link the disease phenotype with a specific gene mutation. In fact, utilizing hiPSC/hESC and CRISPR technology has provided significant insight into the pathomechanism of several diseases. With regard to the eye, the use of hiPSCs/hESCs to study human retinal diseases is especially relevant to retinal pigment epithelium (RPE)-based disorders. This is because several studies have now consistently shown that hiPSC-RPE in culture displays key physical, gene expression and functional attributes of human RPE in vivo. In this book chapter, we will discuss the current utility, limitations, and plausible future approaches of pluripotent stem cell technology for the study of retinal degenerative diseases. Of note, although we will broadly summarize the significant advances made in modeling and studying several retinal diseases utilizing hiPSCs/hESCs, our specific focus will be on the utility of patient-derived hiPSCs for (1) establishment of human cell models and (2) molecular and pharmacological studies on patient-derived cell models of retinal degenerative diseases where RPE cellular defects play a major pathogenic role in disease development and progression.


Assuntos
Células-Tronco Pluripotentes , Degeneração Retiniana , Epitélio Pigmentado da Retina , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas , Retina/patologia , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/patologia
15.
Adv Exp Med Biol ; 1186: 99-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31654387

RESUMO

There is an increasing effort toward generating replacement cells for neuronal application due to the nonregenerative nature of these tissues. While much progress has been made toward developing methodologies to generate these cells, there have been limited improvements in functional restoration. Some of these are linked to the degenerative and often nonreceptive microenvironment that the new cells need to integrate into. In this chapter, we will focus on the status and role of the immune microenvironment of the retina during homeostasis and disease states. We will review changes in both innate and adaptive immunity as well as the role of immune rejection in stem cell replacement therapies. The chapter will end with a discussion of immune-modulatory strategies that have helped to ameliorate these effects and could potentially improve functional outcome for cell replacement therapies for the eye.


Assuntos
Retina , Transplante de Células-Tronco , Imunidade Adaptativa , Microambiente Celular/imunologia , Humanos , Imunidade Inata , Imunomodulação , Neurônios/fisiologia , Retina/imunologia , Degeneração Retiniana/imunologia , Degeneração Retiniana/patologia , Degeneração Retiniana/terapia
16.
Exp Eye Res ; 189: 107852, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31647904

RESUMO

Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We describe a novel fibrovascular proliferation in the retina of two affected members of a KCNJ13-related LCA family with a homozygous c.458C > T, p.(Thr153Ile) missense mutation. Optical coherence tomography retinal imaging of the kcnj13 mutant zebrafish (obelixtd15 c.502T > C, p.[Phe168Leu]) revealed a late onset retinal degeneration at 12 months, with retinal thinning and associated retinovascular changes, including increased vessel calibre and vitreous deposits. Both human and zebrafish variants are missense and located within the conserved transmembrane M2 protein domain, suggesting that disruption of this region may contribute to retinovascular changes as an additional feature to the previously described LCA phenotype. Close monitoring of other patients with similar mutations may be required to minimise the ensuing retinal damage.


Assuntos
Amaurose Congênita de Leber/genética , Mutação de Sentido Incorreto , Canais de Potássio Corretores do Fluxo de Internalização/genética , Retina/metabolismo , Degeneração Retiniana/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , DNA/genética , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Angiofluoresceinografia/métodos , Fundo de Olho , Humanos , Amaurose Congênita de Leber/metabolismo , Amaurose Congênita de Leber/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Domínios Proteicos , Retina/patologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Tomografia de Coerência Óptica/métodos , Adulto Jovem , Peixe-Zebra
17.
Invest Ophthalmol Vis Sci ; 60(13): 4159-4170, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31598627

RESUMO

Purpose: The purpose of this study was to examine the effect of multiple blast exposures and blast preconditioning on the structure and function of retinal ganglion cells (RGCs), to identify molecular pathways that contribute to RGC loss, and to evaluate the role of kynurenine-3-monooxygenase (KMO) inhibition on RGC structure and function. Methods: Mice were subjected to sham blast injury, one single blast injury, or three blast injuries separated by either 1 hour or 1 week, using a blast intensity of 20 PSI. To examine the effect of blast preconditioning, mice were subjected to sham blast injury, one single 20-PSI injury, or three blast injuries separated by 1 week (5 PSI, 5 PSI, 20 PSI and 5 PSI, 5 PSI, 5 PSI). RGC structure was analyzed by optical coherence tomography (OCT) and function was analyzed by the pattern electroretinogram (PERG). BRN3A-positive cells were quantified to determine RGC density. RNA-seq analysis was used to identify transcriptional changes between groups. Results: Analysis of mice with multiple blast exposures of 20 PSI revealed no significant differences compared to one 20-pounds per square inch (PSI) exposure using OCT, PERG, or BRN3A cell counts. Analysis of mice exposed to two preconditioning 5-PSI blasts prior to one 20-PSI blast showed preservation of RGC structure and function. RNA-seq analysis of the retina identified multiple transcriptomic changes between conditions. Pharmacologic inhibition of KMO preserved RGC responses compared to vehicle-treated mice. Conclusions: Preconditioning protects RGC from blast injury. Protective effects appear to involve changes in KMO activity, whose inhibition is also protective.


Assuntos
Traumatismos por Explosões/patologia , Lesões Encefálicas Traumáticas/patologia , Degeneração Retiniana/patologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Animais , Modelos Animais de Doenças , Eletrorretinografia , Quinurenina 3-Mono-Oxigenase/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Retiniana/etiologia , Células Ganglionares da Retina/efeitos dos fármacos , Tomografia de Coerência Óptica
18.
Int J Mol Sci ; 20(18)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546829

RESUMO

Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of "subretinal vascular complexes", vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina.


Assuntos
Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Vasos Retinianos/metabolismo , Animais , Transporte Axonal , Morte Celular , Humanos , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/patologia , Células Ganglionares da Retina/patologia , Epitélio Pigmentado da Retina/patologia , Vasos Retinianos/patologia
19.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557901

RESUMO

Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration.


Assuntos
Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Ratos , Degeneração Retiniana/patologia , Neovascularização Retiniana/patologia , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
20.
Exp Eye Res ; 188: 107816, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31562844

RESUMO

Translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed by reactive microglia and astrocytes at the site of neuronal injury. Although TSPO function has not been fully determined, synthetic TSPO ligands have beneficial effects on different pathologies of the central nervous system, including the retina. Here, we studied the pattern of Tspo expression in the aging human retina and in two mouse models of retinal degeneration. Using a newly generated Tspo-KO mouse, we investigated the impact of the lack of TSPO on retinal morphology, function and susceptibility to degeneration. We show that TSPO was expressed in both human and mouse retina and retinal pigment epithelium (RPE). Tspo was induced in the mouse retina upon degeneration, but constitutively expressed in the RPE. Similarly, TSPO expression levels in healthy human retina and RPE were not differentially regulated during aging. Tspo-KO mice had normal retinal morphology and function up to 48 weeks of age. Photoreceptor loss caused either by exposure to excessive light levels or by a mutation in the phosphodiesterase 6b gene was not affected by the absence of Tspo. The reactivity states of retinal mononuclear phagocytes following light-damage were comparable in Tspo-KO and control mice. Our data suggest that lack of endogenous TSPO does not directly influence the magnitude of photoreceptor degeneration or microglia activation in these two models of retinal degeneration. We therefore hypothesize that the interaction of TSPO with its ligands may be required to modulate disease progression.


Assuntos
Regulação da Expressão Gênica/fisiologia , Receptores de GABA/genética , Degeneração Retiniana/genética , Epitélio Pigmentado da Retina/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Eletrorretinografia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica
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