Osada, Hideto

写真a

Affiliation

School of Medicine, Department of Ophthalmology （Shinanomachi）

Position

Project Assistant Professor (Non-tenured)/Project Research Associate (Non-tenured)/Project Instructor (Non-tenured)
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Research Areas 【 Display / hide 】

  • Life Science / Ophthalmology

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Papers 【 Display / hide 】

  • Effects of Epigenetic Modification of PGC-1α by a Chemical Chaperon on Mitochondria Biogenesis and Visual Function in Retinitis Pigmentosa

    Yoko Ozawa, Eriko Toda, Kohei Homma, Hideto Osada, Norihiro Nagai, Kazuo Tsubota, Hideyuki Okano

    Cells （{MDPI} {AG})  11 （ 9 ） 1497 2022.04

    Accepted,  ISSN  2073-4409

    　View Summary

    <jats:p>Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by gradual photoreceptor death, which lacks a definitive treatment. Here, we demonstrated the effect of 4-phenylbutyric acid (PBA), a chemical chaperon that can suppress endoplasmic reticulum (ER) stress, in P23H mutant rhodopsin knock-in RP models. In the RP models, constant PBA treatment led to the retention of a greater number of photoreceptors, preserving the inner segment (IS), a mitochondrial- and ER-rich part of the photoreceptors. Electroretinography showed that PBA treatment preserved photoreceptor function. At the early point, ER-associated degradation markers, xbp1s, vcp, and derl1, mitochondrial kinetic-related markers, fis1, lc3, and mfn1 and mfn2, as well as key mitochondrial regulators, pgc-1α and tfam, were upregulated in the retina of the models treated with PBA. In vitro analyses showed that PBA upregulated pgc-1α and tfam transcription, leading to an increase in the mitochondrial membrane potential, cytochrome c oxidase activity, and ATP levels. Histone acetylation of the PGC-1α promoter was increased by PBA, indicating that PBA affected the mitochondrial condition through epigenetic changes. Our findings constituted proof of concept for the treatment of ER stress-related RP using PBA and revealed PBA’s neuroprotective effects, paving the way for its future clinical application.</jats:p>

  • Violet light modulates the central nervous system to regulate memory and mood

    Nobunari Sasaki, Pooja Gusain, Motoshi Hayano, Tetsuro Sugaya, Naoya Tonegawa, Yusuke Hatanaka, Risako Tamura, Kei Okuyama, Hideto Osada, Norimitsu Ban, Yasue Mitsukura, Richard A. Lang, Masaru Mimura, Kazuo Tsubota

    （Cold Spring Harbor Laboratory)   2021.11

    　View Summary

    Abstract

    Light stimuli from the external environment serves as a signal. Photoreceptors receive photons at the outer nuclear layer of the retina. Non-visual photoreceptors, such as opsin5 (also known as OPN5 or neuropsin), are expressed in the retinal ganglion cells (RGCs) and hypothalamus to regulate the circadian cycle and body temperature. Here, we show that violet light (VL) stimuli received by OPN5-positive RGCs are transmitted to the habenula brain region. VL improves memory in aged mice and simultaneously increases neural architecture-related genes such as oligodendrocyte-related genes in the hippocampus. In addition, VL improves depressive-like behaviors in the social defeat stress model in an OPN5 dependent manner. Following VL exposure, cFos activation is observed at the nucleus accumbens (NAc) and the paraventricular thalamic nucleus (PVT). Taken together, the results indicate that violet light modulates brain function such as memory and mood by transmitting the signal from RGCs to the habenula region in the brain.

  • Neuroprotective effect of 4-phenylbutyric acid against photo-stress in the retina

    Mendoza N.A.G, Homma K, Osada H, Toda E, Ban N, Nagai N, Negishi K, Tsubota K, Ozawa Y

    Antioxidants （Antioxidants)  10 （ 7 ）  2021.07

    　View Summary

    Exposure to excessive visible light causes retinal degeneration and may influence the progression of retinal blinding diseases. However, there are currently no applied treatments. Here, we focused on endoplasmic reticulum (ER) stress, which can cause cellular degeneration and apoptosis in response to stress. We analyzed functional, histological, and molecular changes in the light-exposed retina and the effects of administering an ER-stress inhibitor, 4-phenylbutyric acid (4-PBA), in mice. We found that light-induced visual function impairment related to photoreceptor cell loss and outer segment degeneration were substantially suppressed by 4-PBA administration, following attenuated photoreceptor apoptosis. Induction of retinal ER stress soon after light exposure, represented by upregulation of the immunoglobulin heavy chain binding protein (BiP) and C/EBP-Homologous Protein (CHOP), were suppressed by 4-PBA. Concurrently, light-induced oxidative stress markers, Nuclear factor erythroid 2–related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1), and mitochondrial apoptotic markers, B-cell lymphoma 2 apoptosis regulator (Bcl-2)-associated death promoter (Bad), and Bcl-2-associated X protein (Bax), were suppressed by 4-PBA administration. Increased expression of glial fibrillary acidic protein denoted retinal neuroinflammation, and inflammatory cytokines were induced after light exposure; however, 4-PBA acted as an anti-inflammatory. Suppression of ER stress by 4-PBA may be a new therapeutic approach to suppress the progression of retinal neurodegeneration and protect visual function against photo-stress.

  • Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium

    Homma K, Toda E, Osada H, Nagai N, Era T, Tsubota K, Okano H, Ozawa Y

    Redox Biology （Redox Biology)  41 2021.05

    ISSN  22132317

    　View Summary

    Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.

  • ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

    Osada H, Toda E, Homma K, Guzman N.A, Nagai N, Ogawa M, Negishi K, Arita M, Tsubota K, Ozawa Y

    Cell Death and Disease （Cell Death and Disease)  12 （ 5 ）  2021.05

    Accepted

    　View Summary

    Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Aerobic exercise protects retinal function in type 2 diabetic mice

    Mamoru Kamoshita, Hideto Osada, Eriko Toda, Kokoro Sano, Motoko Kawashima, Norihiro Nagai, Hajime Shinoda, Kazuo Tsubota, Yoko Ozawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC)  57 ( 12 )  2016.09

    ISSN  0146-0404

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

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

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC)  57 ( 12 )  2016.09

    ISSN  0146-0404

  • AMPK activation protects photoreceptors from light-induced degeneration.

    Hirohiko Kawashima, Hideto Osada, Eriko Toda, Tomohiro Okamoto, Mamoru Kamoshita, Norihiro Nagai, Kazuo Tsubota, Yoko Ozawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC)  57 ( 12 )  2016.09

    ISSN  0146-0404

  • Light-induced retinal degeneration and AMPK

    Hirohiko Kawashima, Hideto Osada, Tomohiro Okamoto, Norimitsu Ban, Mamoru Kamoshita, Toshihide Kurihara, Norihiro Nagai, Kazuo Tsubota, Yoko Ozawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC)  56 ( 7 )  2015.06

    ISSN  0146-0404

  • Neuroprotective effect of rapamycin in the retina

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

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC)  56 ( 7 )  2015.06

    ISSN  0146-0404

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 非視覚型オプシンを介したバイオレットライトによる網膜血管制御機構の解明

    2023.04
    -
    2027.03

    Grants-in-Aid for Scientific Research, 長田 秀斗, Grant-in-Aid for Scientific Research (C), No Setting

    　View Summary

    太陽光に含まれる波長380nmのバイオレットライト(Violet Light: VL)は非視覚光受容体であるOpn5によって受容され、シグナルとして広範囲の組織に影響を及ぼす。近年VLがOpn5を介して網膜血管に対して影響を及ぼすことが報告された。本研究ではVLによる血管新生制御の機構を詳細に検討する。さらに網膜色素上皮における脂質代謝へのVL寄与とその機能の詳細を明らかにし、脈絡膜血管新生に対するVLの影響を示す。以上より、Opn5によって非視覚受容されたVLがいかにして脈絡膜局所の血管形成に対する制御を行うかを明らかにし、VLによる脈絡膜血管新生由来疾患の新規治療法の確立を目指す。

  • Elucidation of retinal degeneration mechanism due to lipid-mediated metabolic disorders

    2019.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Osada Hideto, Grant-in-Aid for Early-Career Scientists , Principal investigator

    　View Summary

    Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in lipid metabolism and retinal neurodegeneration using Adipor1 knockout (KO) mice. Photoreceptors of KO mice were misaligned and their lipid composition, including DHA, which is critical in forming photoreceptor outer segments, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in KO mice. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required in the retinal local lipid metabolism to supply sufficient DHA for appropriate photoreceptor function and survival.

  • The underlying mechanisms of protective role of AdipoR1 on retinal degeneration

    2017.04
    -
    2019.03

    Grants-in-Aid for Scientific Research, Osada Hideto, OZAWA Yoko, Grant-in-Aid for Young Scientists (B), No Setting

    　View Summary

    Adiponectin receptor 1 (AdipoR1) is expressed in various organs, including skeletal muscle, the liver, the spleen, and the retina. AdipoR1 is a well-known receptor of adiponectin, a major regulator of glucose and lipid homeostasis. Recent studies have reported that the mutation of AdipoR1 gene causes retinal degeneration, but its detailed mechanism remains unknown. Here we reported the detailed phenotype of retinal degeneration caused by AdipoR1 mutation. The mutation of AdipoR1 showed the retinal degeneration from very early stage of retinal development, and the severe retinal dysfunction. This indicates the important function of AdipoR1 in retinal development.

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