長田　秀斗 （オサダ　ヒデト）

Osada, Hideto

写真a

所属（所属キャンパス）

医学部 眼科学教室 （信濃町）

職名

特任助教（有期）
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  • ライフサイエンス / 眼科学

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

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

    Cells （{MDPI} {AG}）  11 （ 9 ） 1497 2022年04月

    査読有り,  ISSN  2073-4409

    　概要を見る

    <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年11月

    　概要を見る

    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年07月

    　概要を見る

    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年05月

    ISSN  22132317

    　概要を見る

    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年05月

    査読有り

    　概要を見る

    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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  • 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年09月

    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年09月

    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年09月

    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年06月

    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年06月

    ISSN  0146-0404

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 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年04月
    -
    2027年03月

    科学研究費助成事業, 長田 秀斗, 基盤研究(C), 未設定

    　研究概要を見る

    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。

  • 脂質の介する代謝異常による網膜変性機構の解明

    2019年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 長田　秀斗, 若手研究, 補助金,  研究代表者

    　研究概要を見る

    生活習慣病や臓器機能不全に由来する代謝異常は、網膜の神経変性を引き起こすが、これらは不可逆的変化であり現状治療法はない。網膜は脂質を多量に含有し、形態や光受容体という機能の維持には特定の脂肪酸が必須であることが示唆されている。これら脂肪酸は食物由来であり、多くの臓器による代謝の過程を経て網膜に輸送されるが、肝臓や脂肪の疾患に端を発するような脂質代謝異常が網膜に与える影響には未だ不明な点が多い。本研究では全身の代謝異常に起因する網膜変性の発症機構に関して、組織間を仲介する遠隔メッセージ物質として脂質に着目し、全身性の代謝異常による網膜神経変性を脂質が仲介する機構を明らかにする。
    代謝制御に寄与するアディポネクチン１型受容体(Adipor1)は機能阻害によって網膜色素変性症を呈することが知られているため、Adipor1ノックアウトマウスの網膜および血清を用いてリピドミクス解析を行った。網膜では視細胞外節の形成に重要なDHAを含む脂質の著しい低下を認めた。一方で血清中の脂肪酸の顕著な変化は認めなかった。視細胞内節において発現が認められる脂肪酸伸長酵素Elovl2の発現が低下していた。同時に、脂質合成に関与する多くの遺伝子群の発現が変化しており、Adipor1ノックアウトマウス網膜における局所的な脂質動態の変化が示唆された。
    生活習慣病や臓器機能不全に由来する代謝異常は、糖尿病網膜症をはじめとする網膜の神経変性を引き起こすが、これらは不可逆的変化であり現状治療法はない。網膜は脂質を多量に含有し、形態や光受容体という機能の維持には脂肪酸が必須であることが示唆されている。本研究では網膜変性時の全身および網膜局所の脂質動態の変化を解析することにより、脂質代謝の異常に伴う網膜変性の発症メカニズムを検討した。全身性に変化する物質をとらえることはできなかったものの、網膜局所の脂質動態変化と新たな網膜変性の発生機構を示すことができた。

  • AdipoR1シグナリングの網膜視細胞保護・失明予防の効果のメカニズム

    2017年04月
    -
    2019年03月

    日本学術振興会, 科学研究費助成事業, 長田 秀斗, 小沢 洋子, 若手研究(B), 未設定

    　研究概要を見る

    アディポネクチン1型受容体（Adiponectin receptor 1 ; AdipoR1）は全身で広く発現する内在性膜タンパク質で、脂肪細胞から分泌されるアディポネクチンにより活性化され、骨格筋などではグルコースおよび脂質の代謝を制御している。近年マウス、ヒトにおいてAdipoR1変異による網膜色素変性が報告されており、網膜におけるAdipoR1の重要性が示唆されている。しかし、網膜におけるAdipoR1機能の詳細は依然として不明な点が多い。そこで本研究ではAdipoR1欠損による網膜変性の解析を通じて網膜におけるAdipoR1の機能を明らかにした。
    網膜色素変性症は国内の失明原因の第3位を占め、数多くの原因遺伝子が同定されている。本研究で解析を行ったAdipoR1は近年報告された原因遺伝子であり、発症機構の不明であった網膜色素変性症の一端を明らかにしたことは有意義である。
    また、本研究で着目した網膜という神経組織はこれまでアディポネクチン研究に広く用いられてきた筋肉や脂肪組織とは異なるものである。そのため、いまだ不明な点の多い脳や他の神経系組織におけるアディポネクチンシグナル研究にも役立つような有意義なものであると考えられる。

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