Details of a Researcher - Kurihara, Toshihide

Papers - Kurihara, Toshihide

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Roles of hypoxia response in retinal development and pathophysiology

Kurihara T†

Keio J Med. (Keio Journal of Medicine) 67 ( 1 ) 1 - 9 2018

Accepted, ISSN 00229717

© 2017 by The Keio Journal of Medicine. The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-typespecific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

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Progress and Control of Myopia by Light Environments.

Jiang X, Kurihara T†, Torii H, Tsubota K†

Eye Contact Lens. (Eye and Contact Lens) 44 ( 5 ) 273 - 278 2018

Accepted, ISSN 15422321

Copyright © 2018 Contact Lens Association of Ophthalmologists, Inc. Unauthorized reproduction of this article is prohibited. During the past 30 years, the prevalence rate of myopia has been increased dramatically. Myopia has become one of the leading causes of vision loss in some countries, whereas the mechanism of the main pathological change in myopia is still largely unknown. Although several studies showed genetic background influences the phenotype of myopia to some extent, the sudden increase of morbidity cannot be explained by genetics only. The change in lifestyle results in tremendous change in the light environment, which can be considered to play an important role in the onset and progression of myopia. The difference between indoor and outdoor light environments such as intensity and wavelength of modern electronic lighting equipment may be a cue for myopia control as environmental factors. In this review, we discuss the relationship between myopia and light environment focusing on the basic and clinical studies.

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Elevated Aqueous Cytokine Levels in Eyes With Ocular Surface Diseases.

Aketa N, Yamaguchi T†, Asato T, Yagi-Yaguchi Y, Suzuki T, Higa K, Kurihara T, Satake Y, Tsubota K, Shimazaki J

Am J Ophthalmol. (ELSEVIER SCIENCE INC) 184 42 - 51 2017.12

Accepted, ISSN 0002-9394

PURPOSE: To evaluate cytokine and protein levels in the aqueous humor (AqH) of eyes with ocular surface diseases.
DESIGN: Prospective consecutive case series.
METHODS: This study includes 14 patients (aged 62.4 +/- 13.7 years) with chronic-phase ocular surface diseases (4 with ocular cicatricial pemphigoid, 5 with chemical burns, 2 with a thermal burn, 2 with Stevens-Johnson syndrome, and 1 with exposure keratitis), 14 matched patients without ocular surface disease (controls with corneal scar), and 30 patients who underwent cataract surgery (healthy controls). AqH samples were collected at the beginning of surgery. AqH levels of cytokines (interleukin [IL]-1 alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, monocyte chemotactic protein [MCP]-1, interferon [IFN]-alpha, IFN-gamma, macrophage inflammatory protein [MIP]-1 alpha, MIP-1 beta, P-selectin, E-selectin, soluble-intercellular adhesion molecule [s-ICAM]-1, tumor necrosis factor [TNF]-alpha, granulocyte-macrophage colony-stimulating factor [GMCSF], IFN-gamma-induced protein [IP]-10) were measured using multiplex beads immunoassays.
RESULTS: The levels of IL-6, IL-10, IL-17A, GM-CSF, E-selectin, P-selectin, and s-ICAM in AqH were significantly elevated in eyes with ocular surface diseases (in pg/mL: 1696 +/- 804, 4.0 +/- 1.0, 24.3 +/- 9.8, 26.0 +/- 18.3, 5150 +/- 1232, 13122 +/- 7219, and 7914 +/- 2813, respectively), compared to healthy controls (IL-6: 6.36 +/- 0.94, P = .001; IL-10: 1.68 +/- 0.04, P = .0006; IL-17A: 3.7 +/- 0.2, P = .008; GM-CSF: 2.7 +/- 0.3, P = .007; E-selectin: 2093 +/- 37, P = .0001; P-selectin: 3658 +/- 137, P = .0001; sICAM-1: 1397 +/- 119, P = .008). The levels of IL-6, IL-17A, E-selectin, and P-selectin in AqH were significantly higher in eyes with ocular surface diseases compared to those with corneal scar (IL-6: 44.1 +/- 15.0, P = .0077; IL-17A: 4.1 +/- 0.7, P = .034; E-selectin: 2439 +/- 302, P = .039; and P-selectin: 5673 +/- 1553, P = .017).
CONCLUSIONS: Multiple AqH cytokine levels were elevated in chronic ocular surface diseases. ((C) 2017 Elsevier Inc. All rights reserved.)

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Violet Light Transmission is Related to Myopia Progression in Adult High Myopia

Torii H, Ohnuma K, Kurihara T, Tsubota K, Negishi K†

Sci Rep. (NATURE PUBLISHING GROUP) 7 ( 1 ) 14523 2017.11

Accepted, ISSN 2045-2322

Myopia is increasing worldwide. Although the exact etiology of myopia is unknown, outdoor activity is one of the most important environmental factors for myopia control. We previously reported that violet light (VL, 360-400 nm wavelength), which is abundant in the outdoor environment, suppressed myopia progression for individuals under 20 years of age. However, whether VL is also effective for adult high myopia, which can be sight-threatening, has remained unknown. To investigate the influence of VL for adult myopia, we retrospectively compared the myopic progression and the axial length elongation over five years in adult high myopic patients over 25 years of age after two types (non-VL transmitting and VL transmitting) of phakic intraocular lens (pIOL) implantation. We found that high myopic patients with the non-VL transmitting pIOLs implanted are almost two times more myopic in the change of refraction and four times longer in the change of axial length, compared to those implanted with the VL transmitting pIOLs. This result indicated that the VL transmitting pIOL suppressed myopia progression and axial length elongation compared with the non-VL transmitting one. In conclusion, our study showed the VL possibly has an anti-myopia effect for human adults with high myopia.

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Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration.

Ozawa Y*†, Shigeno Y*, Nagai N, Suzuki M, Kurihara T, Minami S, Hirano E, Shinoda H, Kobayashi S, Tsubota K

BMC Ophthalmol. (BIOMED CENTRAL LTD) 17 ( 1 ) 161 2017.08

Accepted, ISSN 1471-2415

Background: Lutein and zeaxanthin are suggested micronutrient supplements to prevent the progression of age-related macular degeneration (AMD), a leading cause of blindness worldwide. To monitor the levels of lutein/zeaxanthin in the macula, macular pigment optical density (MPOD) is measured. A commercially available device (MPSII (R), Elektron Technology, Switzerland), using technology based on heterochromatic flicker photometry, can measure both absolute and estimated values of MPOD. However, whether the estimated value is applicable to Asian individuals and/or AMD patients remains to be determined.
Methods: The absolute and estimated values of MPOD were measured using the MPSII (R) device in 77 participants with a best-corrected visual acuity (BCVA) > 0.099 (logMAR score).
Results: The studied eyes included 17 young (20-29 years) healthy, 26 aged (> 50 years) healthy, 18 aged and AMD-fellow, and 16 aged AMD eyes. The mean BCVA among the groups were not significantly different. Both absolute and estimated values were measurable in all eyes of young healthy group. However, absolute values were measurable in only 57.7%, 66.7%, and 43.8%, of the aged healthy, AMD-fellow, and AMD groups, respectively, and 56.7% of the eyes included in the 3 aged groups. In contrast, the estimated value was measurable in 84.6%, 88.9% and 93.8% of the groups, respectively, and 88.3% of eyes in the pooled aged group. The estimated value was correlated with absolute value in individuals from all groups by Spearman's correlation coefficient analyses (young healthy: R-2 = 0.885, P = 0. 0001; aged healthy: R-2 = 0.765, P = 0.001; AMD-fellow: R-2 = 0.851, P = 0.0001; and AMD: R-2 = 0.860, P = 0.013). Using the estimated value, significantly lower MPOD values were found in aged AMD-related eyes, which included both AMD-fellow and AMD eyes, compared with aged healthy eyes by Student's t-test (P = 0.02).
Conclusions: Absolute, in contrast to estimated, value was measurable in a limited number of aged participants; however, it was correlated with estimated value both in young and aged Asian populations with or without AMD. These results may inform future clinical studies investigating the measurement of MPOD in understanding the role of macular pigments in the pathogenesis of AMD.

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Predictive factors of better outcomes by monotherapy of an antivascular endothelial growth factor drug, ranibizumab, for diabetic macular edema in clinical practice.

Sato S, Shinoda H, Nagai N, Suzuki M, Uchida A, Kurihara T, Kamoshita M, Tomita Y, Iyama C, Minami S, Yuki K, Tsubota K, Ozawa Y†

Medicine. (LIPPINCOTT WILLIAMS & WILKINS) 96 ( 16 ) e6459 2017.04

Accepted, ISSN 0025-7974

Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known.
The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated.
Twenty-five eyes from 25 patients (16 men; mean age 68.7+/-9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (P=.003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (r=-.57; P=.003) and CRT (r=-.60; P=.002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (P=.026). After adjusting for age and sex, CRT improvement >100 mu m at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10 mu m [95% CI 0.72-0.97]; P=.018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (r= 0.77; P<.001) and lower CRT (r=0.41; P=.039) at baseline, respectively, according to linear regression analyses.
IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted.

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Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression.

Torii H, Kurihara T, Seko Y, Negishi K, Ohnuma K, Inaba T, Kawashima M, Jiang X, Kondo S, Miyauchi M, Miwa Y, Katada Y, Mori K, Kato K, Tsubota K, Goto H, Oda M, Hatori M, Tsubota K†

EBioMedicine. (ELSEVIER SCIENCE BV) 15 210 - 219 2017.02

Accepted, ISSN 2352-3964

Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400 nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment

Nagai, Norihiro, Suzuki, Misa, Uchida, Atsuro, Kurihara, Toshihide, Kamoshita, Mamoru, Minami, Sakiko, Shinoda, Hajime, Tsubota, Kazuo, Ozawa, Yoko

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 6 52 - 59 2016.07

Research paper (scientific journal), Accepted, ISSN 2045-2322

The prognosis of neovascular age-related macular degeneration (AMD) has been improved by anti-vascular endothelial growth factor treatments, including intravitreal aflibercept (IVA) treatment. However, many patients remain incurable. In this study, we retrospectively evaluated non-responsiveness to IVA monotherapy at 12 months in 133 eyes of 133 AMD patients. Sixty-two patients were initially treatment-naive, and 71 had received other treatments before IVA (the treatment-switched group). Mean best-corrected visual acuity (BCVA) was improved in the treatment-naive group but not in the treatment-switched group, although mean central retinal thickness (CRT) decreased in both groups. The respective percentages of non-responders as determined by worsened BCVA in the treatment-naive and treatment-switched groups were 8.1% and 15.5%, and via fundus findings, they were 12.9% and 8.5%. Multivariate analyses adjusted for age, gender, CRT, and greatest linear dimension showed that serous pigment epithelial detachment (PED) at baseline was associated with non-responsiveness in both groups as determined by BCVA and by fundus findings, and fibrovascular PED measurements indicated no response as determined by fundus findings in the treatment-switched group. The results reported herein may assist the formulation of appropriate treatment protocols for AMD patients.

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Distinct Responsiveness to Intravitreal Ranibizumab Therapy in Polypoidal Choroidal Vasculopathy With Single or Multiple Polyps

Suzuki, Misa, Nagai, Norihiro, Shinoda, Hajime, Uchida, Atsuro, Kurihara, Toshihide, Tomita, Yohei, Kamoshita, Mamoru, Iyama, Chigusa, Tsubota, Kazuo, Ozawa, Yoko

AMERICAN JOURNAL OF OPHTHALMOLOGY (ELSEVIER SCIENCE INC) 166 52 - 59 2016.06

Research paper (scientific journal), Accepted, ISSN 0002-9394

PURPOSE: To understand the prognosis of polypoidal choroidal vasculopathy (PCV) by evaluating the responsiveness to intravitreal ranibizumab (IVR) monotherapy according to the presence of a single or multiple polyps.
DESIGN: Retrospective case series.
METHODS: We included 48 treatment-naive eyes of 48 patients who received IVR monotherapy at the Medical Retina Division Clinic, Keio University Hospital between March 2009 and January 2013 and attended the clinic for at least 12 months. All patients received 3 monthly IVR injections followed by pro re nata injections and were divided into single polyp and multiple polyps groups according to indocyanine green angiography and optical coherence tomography (OCT) findings. The outcome measures included changes in best corrected visual acuity (BCVA) and OCT findings over 2 years after initial IVR.
RESULTS: At baseline, the multiple polyps group exhibited a poorer BCVA, larger greatest linear dimension, and higher prevalence of fibrovascular pigment epithelial detachment compared with the single polyp group. Over 2 years, the multiple polyps group showed no improvement in BCVA, although the central retinal thickness (CRT) decreased in both groups. The multiple polyps group exhibited a significantly greater CRT at 1 year and required more injections in the first year compared with the single polyp group; furthermore, it included a higher number of nonresponders judged either by BCVA or fundus findings at 1 year and fundus findings at 2 years.
CONCLUSIONS: We propose that the stratification of PCV lesions according to the presence of single or multiple polyps may be valuable to understand the prognosis. (C) 2016 The Authors. Published by Elsevier Inc.

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Development and pathological changes of neurovascular unit regulated by hypoxia response in the retina.

Kurihara T†

Prog Brain Res. (ELSEVIER SCIENCE BV) 225 201 - 211 2016.04

Lead author, Last author, Corresponding author, Accepted, ISSN 0079-6123

Retina is a highly vascularized tissue with a high oxygen and metabolic demand receiving light located in the back of the eye. The development and the maintenance of the retinal vasculature are important to regulate the homeostasis in the tissue. a Subunits of hypoxia-inducible factor (HIF) are key molecules in hypoxia response inducing genes required for cell survival such as vascular endothelial growth factor under hypoxia. Neurons, glia, and vascular endothelium cells interdependently form neurovascular unit in the retina tightly regulated by hypoxia response via HIF expression. A corruption of the precise hypoxia response in the developmental or matured retinal tissue may lead congenital vascular anomalies or adult neovascular ocular diseases. To regulate hypoxia response through HIF activity would be an ideal therapeutic target for these vision-threatening eye diseases.

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Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

Kurihara, Toshihide, Westenskow, Peter D., Gantner, Marin L., Usui, Yoshihiko, Schultz, Andrew, Bravo, Stephen, Aguilar, Edith, Wittgrove, Carli, Friedlander, Mollie S. H., Paris, Liliana P., Chew, Emily, Siuzdak, Gary, Friedlander, Martin

ELIFE (ELIFE SCIENCES PUBLICATIONS LTD) 5 52 - 59 2016.03

Research paper (scientific journal), Accepted, ISSN 2050-084X

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

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iPSC-Derived Retinal Pigment Epithelium Allografts Do Not Elicit Detrimental Effects in Rats: A Follow-Up Study.

Westenskow PD, Bucher F, Bravo S, Kurihara T, Feitelberg D, Paris LP, Aguilar E, Lin JH, Friedlander M†

Stem Cells Int. (HINDAWI LTD) 2016 Article ID 8470263 2016.01

Accepted, ISSN 1687-966X

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 21/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.

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Global metabolomics reveals metabolic dysregulation in ischemic retinopathy

Paris, Liliana P., Johnson, Caroline H., Aguilar, Edith, Usui, Yoshihiko, Cho, Kevin, Hoang, Lihn T., Feitelberg, Daniel, Benton, H. Paul, Westenskow, Peter D., Kurihara, Toshihide, Trombley, Jennifer, Tsubota, Kinya, Ueda, Shunichiro, Wakabayashi, Yoshihiro, Patti, Gary J., Ivanisevic, Julijana, Siuzdak, Gary, Friedlander, Martin

METABOLOMICS (SPRINGER) 12 ( 1 ) 52 - 59 2016.01

Research paper (scientific journal), Accepted, ISSN 1573-3882

Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets. Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (n = 9) and non-diabetic controls (n = 11) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (n = 11) and non-diabetic controls (n = 20)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to-proline pathway could be used as a therapeutic target in diabetic retinopathy.

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The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-kappa B Axis during Retinal Inflammation

Okamoto, Tomohiro, Ozawa, Yoko, Kamoshita, Mamoru, Osada, Hideto, Toda, Eriko, Kurihara, Toshihide, Nagai, Norihiro, Umezawa, Kazuo, Tsubota, Kazuo

PLOS ONE (PUBLIC LIBRARY SCIENCE) 11 ( 1 ) 52 - 59 2016.01

Research paper (scientific journal), Accepted, ISSN 1932-6203

Purpose
The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.
Methods
The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS) length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.
Results
The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-kappa B activation, mTOR inhibition suppressed NF-kappa B activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF-kappa B in the retina. In addition, the inhibition of NF-kappa B suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-kappa B during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin.
Conclusions
Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTOR levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation.

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Effects of Constant Intake of Lutein-rich Spinach on Macular Pigment Optical Density: a Pilot Study

Ozawa Y†, Nagai N, Suzuki M, Kurihara T, Shinoda H, Watanabe M, Tsubota K

Nippon Ganka Gakkai zasshi 120 ( 1 ) 41 - 48 2016.01

Accepted, ISSN 0029-0203

Wide-Angle Viewing System versus Conventional Indirect Ophthalmoscopy for Scleral Buckling

Tomita, Yohei, Kurihara, Toshihide, Uchida, Atsuro, Nagai, Norihiro, Shinoda, Hajime, Tsubota, Kazuo, Ozawa, Yoko

SCIENTIFIC REPORTS (NATURE PUBLISHING GROUP) 5 275 - 281 2015.09

Research paper (scientific journal), Accepted, ISSN 2045-2322

Wide-angle viewing systems (WAVSs) were originally established for pars plana vitrectomy. However, their application to scleral buckling surgery was recently reported. In this study, we compared the outcomes of scleral buckling using a noncontact WAVS with that of scleral buckling using conventional indirect ophthalmoscopy for rhegmatogenous retinal detachment. The clinical records of 39 eyes (39 patients) with rhegmatogenous retinal detachment primarily treated between November 2012 and June 2014 at the Vitreo-Retina Surgical Division Clinic at the Department of Ophthalmology, Keio University Hospital were retrospectively reviewed. Scleral bucking was performed using WAVS with surgical placement of an endoilluminator in 16 eyes and indirect ophthalmoscopy in 23 eyes. The patients in these groups were consecutive over different intervals. The preoperative demographics, success rate of retinal reattachment, intraoperative findings, and postoperative complications were evaluated. There were no significant differences in pre- or postoperative conditions between groups, and similar surgical outcomes were achieved with the WAVS and conventional procedures. However, compared with the conventional procedure, the WAVS procedure resulted in fewer intraoperative corneal epithelial disorders (p = 0.049) and decreased the surgical duration of segmental buckling (p = 0.02); therefore, it may be suggested as an effective alternative procedure.

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Neurovascular crosstalk between interneurons and capillaries is required for vision

Usui, Voshihiko, Westenskow, Peter D., Kurihara, Toshihide, Aguilar, Edith, Sakimoto, Susumu, Paris, Liliana P., Wittgrove, Carli, Feitelberg, Daniel, Friedlander, Mollie S. H., Moreno, StaceyR., Dorrell, Michael I., Friedlander, Martin

JOURNAL OF CLINICAL INVESTIGATION (AMER SOC CLINICAL INVESTIGATION INC) 125 ( 6 ) 2335 - 2346 2015.06

Research paper (scientific journal), Accepted, ISSN 0021-9738

Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. For example, the architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. Here, using murine genetic models and cell ablation strategies, we have demonstrated that a subset of retinal interneurons, the amacrine and horizontal cells, form neurovascular units with capillaries in 2 of the 3 retinal vascular plexuses. Moreover, we determined that these cells are required for generating and maintaining the intraretinal vasculature through precise regulation of hypoxia-inducible and proangiogenic factors, and that amacrine and horizontal cell dysfunction induces alterations to the intraretinal vasculature and substantial visual deficits. These findings demonstrate that specific retinal interneurons and the intraretinal vasculature are highly interdependent, and loss of either or both elicits profound effects on photoreceptor survival and function.

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Blue light-induced inflammatory marker expression in the retinal pigment epithelium-choroid of mice and the protective effect of a yellow intraocular lens material in vivo

Narimatsu, Toshio, Negishi, Kazuno, Miyake, Seiji, Hirasawa, Manabu, Osada, Hideto, Kurihara, Toshihide, Tsubota, Kazuo, Ozawa, Yoko

EXPERIMENTAL EYE RESEARCH 132 48 - 51 2015.03

Research paper (scientific journal), Accepted, ISSN 0014-4835

Oxidative stress in the retinal pigment epithelium (RPE) is a well-accepted pathogenic change in vision-threatening diseases such as age-related macular degeneration. One source of oxidative stress is excessive light exposure, which causes excessive activation of the visual cycle. Because short wavelength light (blue light) has more energy, it is reported to be more harmful to photoreceptor cells than the other wavelengths of light. However, the biological effect of blue light in the RPE of living animals and the protective effect of a yellow intraocular lens (IOL) material that blocks blue light is still obscure. Therefore, we compared the pathogenic effect in the RPE-choroid complexes of mice exposed to light in a box made of a clear or a yellow IOL material. We measured the level of reactive oxygen species (ROS) using 2', 7'-dichlorodihydrofluorescein diacetate, the mRNA levels of inflammatory cytokines and a macrophage marker by real-time polymerase chain reaction, and the protein level of monocyte chemotactic protein-1 (MCP-1) by ELISA. The ROS level after light exposure was suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. In parallel, all the inflammatory cytokines that we measured and a macrophage marker were also suppressed in the RPE-choroids of light-exposed mice in the yellow IOL material box. Therefore, a yellow IOL material suppressed, and thus blue light exacerbated, the increase in the ROS level and inflammatory cytokine expression as well as macrophage recruitment in the RPE-choroid in vivo after light exposure.

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Performing Subretinal Injections in Rodents to Deliver Retinal Pigment Epithelium Cells in Suspension

Westenskow, Peter D., Kurihara, Toshihide, Bravo, Stephen, Feitelberg, Daniel, Sedillo, Zack A., Aguilar, Edith, Friedlander, Martin

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS (JOURNAL OF VISUALIZED EXPERIMENTS) 23 ( 95 ) 2335 - 2346 2015.01

Research paper (scientific journal), Accepted, ISSN 1940-087X

The conversion of light into electrical impulses occurs in the outer retina and is accomplished largely by rod and cone photoreceptors and retinal pigment epithelium (RPE) cells. RPE provide critical support for photoreceptors and death or dysfunction of RPE cells is characteristic of age-related macular degeneration (AMD), the leading cause of permanent vision loss in people age 55 and older. While no cure for AMD has been identified, implantation of healthy RPE in diseased eyes may prove to be an effective treatment, and large numbers of RPE cells can be readily generated from pluripotent stem cells. Several interesting questions regarding the safety and efficacy of RPE cell delivery can still be examined in animal models, and well-accepted protocols used to inject RPE have been developed. The technique described here has been used by multiple groups in various studies and involves first creating a hole in the eye with a sharp needle. Then a syringe with a blunt needle loaded with cells is inserted through the hole and passed through the vitreous until it gently touches the RPE. Using this injection method, which is relatively simple and requires minimal equipment, we achieve consistent and efficient integration of stem cell-derived RPE cells in between the host RPE that prevents significant amount of photoreceptor degeneration in animal models. While not part of the actual protocol, we also describe how to determine the extent of the trauma induced by the injection, and how to verify that the cells were injected into the subretinal space using in vivo imaging modalities. Finally, the use of this protocol is not limited to RPE cells; it may be used to inject any compound or cell into the subretinal space.

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Neurons Limit Angiogenesis by Titrating VEGF in Retina

Okabe, Keisuke, Kobayashi, Sakiko, Yamada, Toru, Kurihara, Toshihide, Tai-Nagara, Ikue, Miyamoto, Takeshi, Mukouyama, Yoh-suke, Sato, Thomas N., Suda, Toshio, Ema, Masatsugu, Kubota, Yoshiaki

CELL (CELL PRESS) 159 ( 3 ) 584 - 596 2014.10

Research paper (scientific journal), Accepted, ISSN 0092-8674

Vascular and nervous systems, two major networks in mammalian bodies, show a high degree of anatomical parallelism and functional crosstalk. During development, neurons guide and attract blood vessels, and consequently this parallelism is established. Here, we identified a noncanonical neurovascular interaction in eye development and disease. VEGFR2, a critical endothelial receptor for VEGF, was more abundantly expressed in retinal neurons than in endothelial cells, including endothelial tip cells. Genetic deletion of VEGFR2 in neurons caused misdirected angiogenesis toward neurons, resulting in abnormally increased vascular density around neurons. Further genetic experiments revealed that this misdirected angiogenesis was attributable to an excessive amount of VEGF protein around neurons caused by insufficient engulfment of VEGF by VEGFR2-deficient neurons. Moreover, absence of neuronal VEGFR2 caused misdirected regenerative angiogenesis in ischemic retinopathy. Thus, this study revealed neurovascular crosstalk and unprecedented cellular regulation of VEGF: retinal neurons titrate VEGF to limit neuronal vascularization.

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