2022/07/01 更新

写真a

ハラ タカユキ
原 孝行
HARA Takayuki
所属
岡山大学病院 助教(特任)
職名
助教(特任)
外部リンク

学位

  • 医学 ( 2015年9月   岡山大学 )

研究分野

  • ライフサイエンス / 代謝、内分泌学

経歴

  • 岡山大学病院   医療安全管理部   助教

    2022年1月 - 現在

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  • 岡山大学   腎臓・糖尿病・内分泌内科   助教

    2019年7月 - 2021年12月

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  • 岡山大学   医歯薬学総合研究科   助教

    2019年1月 - 2019年6月

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  • 岡山大学   医員

    2012年4月 - 2018年12月

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論文

  • An adrenal incidentaloma caused by synchronous and isolated metastasis. 国際誌

    Koichiro Yamamoto, Kosuke Oka, Hiroyuki Honda, Kou Hasegawa, Yoshihisa Hanayama, Tomofumi Watanabe, Yusuke Tominaga, Atsushi Takamoto, Takayuki Hara, Fumio Otsuka

    Clinical case reports   9 ( 4 )   2494 - 2495   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report a patient with adrenal incidentaloma due to synchronous and isolated metastasis from lung cancer, which is a relatively rare condition. Close checkups for incidentaloma in oncologic patients are mandatory, leading to successful operation.

    DOI: 10.1002/ccr3.3996

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  • Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report. 査読 国際誌

    Natsumi Matsuoka, Kenji Tsuji, Eiki Ichihara, Takayuki Hara, Kazuhiko Fukushima, Kishio Toma, Shinji Kitamura, Kenichi Inagaki, Hitoshi Sugiyama, Jun Wada

    BMC nephrology   21 ( 1 )   113 - 113   2020年3月

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    記述言語:英語  

    BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. CASE PRESENTATION: A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. CONCLUSION: All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

    DOI: 10.1186/s12882-020-01775-z

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  • Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions 査読

    Motoshi Komatsubara, Takayuki Hara, Takeshi Hosoya, Kishio Toma, Naoko Tsukamoto-Yamauchi, Nahoko Iwata, Kenichi Inagaki, Jun Wada, Fumio Otsuka

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   165 ( Pt B )   182 - 189   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-beta-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and CAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smac16/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and glucocorticoid in the adrenal medulla. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2016.06.002

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  • Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells 査読

    Takayuki Hara, Fumio Otsuka, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Takeshi Hosoya, Eri Nakamura, Tomohiro Terasaka, Motoshi Komatsubara, Hirofumi Makino

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   152   8 - 15   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PICA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, CAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both rnelatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PICA pathway. The results also suggested that mutual enhancement of melatonin and activin receptor signaling is involved in the induction of aldosterone output by adrenocortical cells. (C) 2015 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2015.04.012

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  • Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells 査読

    Takeshi Hosoya, Fumio Otsuka, Eri Nakamura, Tomohiro Terasaka, Kenichi Inagaki, Naoko Tsukamoto-Yamauchi, Takayuki Hara, Kishio Toma, Motoshi Komatsubara, Hirofumi Makino

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   147   85 - 91   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    BMPs expressed in the ovary differentially regulate steroidogenesis by granulosa cells. BMP-9, a circulating BMP, is associated with cell proliferation, apoptosis and differentiation in various tissues. However, the effects of BMP-9 on ovarian function have yet to be elucidated. Here we investigated BMP-9 actions on steroidogenesis using rat primary granulosa cells. BMP-9 potently suppressed FSH-induced progesterone production, whereas it did not affect FSH-induced estradiol production by granulosa cells. The effects of BMP-9 on FSH-induced steroidogenesis were not influenced by the presence of oocytes. FSH-induced cAMP synthesis and FSH-induced mRNA expression of steroidogenic factors, including StAR, P450scc, 3 beta HSD2 and FSHR, were suppressed by treatment with BMP-9. BMP-9 mRNA expression was detected in granulosa cells but not in oocytes. BMP-9 readily activated Smad1/5/8 phosphorylation and Id-1 transcription in granulosa cells. Analysis using ALK inhibitors indicated that BMP-9 actions were mediated via type-I receptors other than ALK-2, -3 and -6. Furthermore, experiments using extracellular domains (ECDs) for BMP type-I and -II receptor constructs revealed that the effects of BMP-9 were reversed by ECDs for ALK-1 and BMPRII. Thus, the functional receptors for BMP-9 in granulosa cells were most likely to be the complex of ALK-1 and BMPRII. Collectively, the results of the present study showed that BMP-9 can affect luteinization and that there are two possible sources of BMP-9, serum and granulosa cells in the ovary. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2014.12.007

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  • Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis 査読

    Hidetoshi Kagawa, Tsutomu Hiromasa, Takayuki Hara, Ayako Takaki, Ryutaro Yamanaka, Ken-ei Sada, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 5 )   760 - 766   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.
    We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.
    All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.
    This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

    DOI: 10.1007/s10157-012-0632-4

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共同研究・競争的資金等の研究

  • 副腎皮質におけるBMPシステムの役割と血圧調整への作用

    研究課題/領域番号:20K17512  2020年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    原 孝行

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    高血圧は最も多い生活習慣病であり、特にメタボリックシンドローム・肥満患者の高血圧にはレニン・アンギオテンシン・アルドステロン系の亢進が関与するとされ、脳心血管合併症予防にその制御が重要である。我々は副腎皮質内にBMPシステムが存在し、BMP-6およびActivinがそれぞれAng II-MAPK・ACTH-cAMP/PKAを介してアルドステロン分泌調節に寄与することを報告してきた。BMP-9は他のBMPと比べ高濃度で循環血液中に存在し、循環因子としての機能が注目され、糖尿病や脂質異常症など生活習慣病との関連が示唆されているが、副腎への作用は明らかになっていない。本研究では副腎皮質におけるBMP-9の役割について検討した。BMP-9はヒトH295R細胞でのコルチゾールおよびアルドステロン基礎分泌には影響を与えなかった。また、高カリウム状態でのホルモン産生には有意な変化がなかったが、一方、BMP-9はAngIIによるコルチゾール分泌に弱い抑制作用を示し、さらにforskolinおよびdibutyryl-cAMPで誘導されるステロイド合成酵素(StAR・CYP11B2、CYP17)のmRNAレベルを減弱し、cAMPを低下させることで、コルチゾールおよびアルドステロン分泌を抑制した。また、副腎皮質での細胞内シグナル伝達としてBMP-9はSmad1/5/8のリン酸化を介することが示された。以上の点より、BMP-9は副腎皮質においてcAMP-PKA経路を抑制することで副腎皮質ステロイド産生を抑制することが示唆された。

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