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Ishigami Akihito

    Vice-president ( Biology and Medical Sciences )　Vice-president
Last Updated :2024/12/27

Researcher Information

Alias Name

    K11J010129H

URL

J-Global ID

Research Interests

  • senescent cells   Nutrition   老化   ビタミンC   シトルリン化蛋白質   PAD   SMP30   老化制御   

Academic & Professional Experience

  • 2023/04 - Today  Tokyo Metropolitan Institute for Geriatrics and GerontologyVice-president
  • 2014/04 - 2023/03  地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所)老化制御研究チーム 分子老化制御研究部長 チームリーダー
  • 2011/04 - 2014/03  Tokyo Metropolitan Institute of Gerontology老化制御研究チーム 分子老化制御研究副部長
  • 2008/04 - 2011/03  東邦大学薬学部生化学准教授
  • 2005/04 - 2008/03  東京都老人総合研究所老化制御リーダー・主任研究員
  • 1994/01 - 2005/03  東京都老人総合研究細胞化学部門研究員
  • 1992/05 - 1993/12  米国国立衛生研究所 (NIH) 米国国立老化研究所 (NIA)客員研究員

Association Memberships

  • 日本ビタミン学会   日本分子生物学会   日本生化学会   日本薬学会   日本老年医学会   日本基礎老化学   

Published Papers

Books etc

  • 日本ビタミン学会; 竹谷, 豊; 生城, 浩子; 池田, 彩子; 石川, 考博; 太田, 好次; 小暮, 健太朗; 瀧谷, 公隆; 田中, 清; 津川, 尚子; 内藤, 裕二; 野坂, 和人; 福渡, 努 (Contributor生理学(生理機能)、栄養学(欠乏症)、トピックス(ビタミンCとエピジェネテックス))朝倉書店 2021/07 9784254102925 xv, 635p
  • 末光, 隆志 (Contributor寿命と成長)朝倉書店 2020/11 9784254171662 xxiii, 746p
  • 石井, 敏浩; 田中, 博之; 石神, 昭人; 渡辺, 朋子 (Joint editor老化のメカニズムと制御)京都廣川書店 2019/09 9784909197511 vii, 128p
  • 糸川, 嘉則 (ContributorビタミンC誘導体の開発)シーエムシー出版 2018/01 9784781312217 vii, 221p
  • Protein Deimination in Human Health and Disease
    Kondo Y. Choi; E.K. Kim; Y.S. Ishigami A (ContributorUpdate on Deimination in Alzheimer’s Disease)2017
  • 中野, 展子; 石神, 昭人 (Joint work)東京堂出版 2014/07 9784490108491 234p
  • Erdman, John W.; Macdonald, Ian; Zeisel, Steven H.; 小川, 佳宏; 桑田, 有; 駒井, 三千夫; 武田, 英二; 徳留, 信寛; 伏木, 亨; 渡邊, 敏明; 木村, 修一; 古野, 純典 (Joint translationChapter16ビタミンC)建帛社 2014/05 9784767961750 vii, 1133p
  • 前田, 憲寿 (Contributor皮膚老化とビタミンC)シーエムシー出版 2014/04 9784781309385 xi, 271p
  • Protein Deimination in Human Health and Disease
    Choi E.K. Jang; B. Ishigami; A. Maruyama; N. Carp; R.I. Kim Y; K (ContributorDeimination in Prion Diseases)2014
  • Protein Deimination in Human Health and Disease
    Ishigami A. Choi E.K., Kim Y.S., Maruyama N (ContributorDeimination in Alzheimer’s Disease)2014
  • Ageing：Oxidative Stress and Dietary Antioxidants
    Saito K; Hosoi E; Ishigami A; Yokoyama T (ContributorVitamin C and Physical Performance in the Elderly)Elsevier 2014
  • 石神, 昭人 (Single work)東京堂出版 2011/11 9784490108101 243p
  • 日本ビタミン学会 (ContributorビタミンC)朝倉書店 2010/11 9784254102284 xx, 624p, 図版 [4] p
  • 大熊, 勝治; 中西, 義信 (Contributorタンパク質の細胞内導入法)廣川書店 2010/03 9784567170505 xiv, 271p
  • 大内, 尉義; 秋山, 弘子; 折茂, 肇 (Contributorタンパク質の加齢変化)東京大学出版会 2010/01 9784130664066 xxxvii, 2142p
  • Handbook of Vitamin C Research: Daily Requirements, Dietary Sources and Adverse Effects
    Ishigami A (ContributorShortage of Vitamin C Accelerates Aging)2009
  • 日本基礎老化学会 (ContributorSMP30/GNLノックアウトマウス)アドスリー,丸善 (発売) 2008/05 9784900659902 293p
  • 松尾, 光芳 (Contributor栄養制限下における物質代謝)学会出版センター 1994/04 4762277622 ix, 223p
  • Goto, S., Ishigami, A. and Takahashi, R. : Effect of age and dietary restriction on accumulation of altered proteins and degradation of proteins in mouse. In: Liver and Aging--1990. Kitani, K. (Ed.), Amsterdam: Elsevier Science Publishers B.V., pp.137-・・・
    Goto, S., Ishigami, A. and Takahashi, R. : Effect of age and dietary restriction on accumulation of altered proteins and degradation of proteins in mouse. In: Liver and Aging--1990. Kitani, K. (Ed.), Amsterdam: Elsevier Science Publishers B.V., pp.137-147 (1991)
  • Kurochkin, I.V., Takahashi, R., Ishigami, A., Fujita, Y. and Goto, S. : Age-related change in the proteolytic activity on the high molecular mass ATP-stimulated protease from mouse liver. In: New Horizons in Aging Science. Orimo, H. (Ed.), Japan: Univ.・・・
    Kurochkin, I.V., Takahashi, R., Ishigami, A., Fujita, Y. and Goto, S. : Age-related change in the proteolytic activity on the high molecular mass ATP-stimulated protease from mouse liver. In: New Horizons in Aging Science. Orimo, H. (Ed.), Japan: Univ. of Tokyo Press, pp.57-58 (1992)
  • Goto, S., Ishigami, A. and Takahashi, R. : Effect of age and dietary restriction on accumulation of altered proteins and degradation of proteins in mouse. In: Liver and Aging--1990. Kitani, K. (Ed.), Amsterdam: Elsevier Science Publishers B.V., pp.137-・・・
    Goto, S., Ishigami, A. and Takahashi, R. : Effect of age and dietary restriction on accumulation of altered proteins and degradation of proteins in mouse. In: Liver and Aging--1990. Kitani, K. (Ed.), Amsterdam: Elsevier Science Publishers B.V., pp.137-147 (1991)
  • Kurochkin, I.V., Takahashi, R., Ishigami, A., Fujita, Y. and Goto, S. : Age-related change in the proteolytic activity on the high molecular mass ATP-stimulated protease from mouse liver. In: New Horizons in Aging Science. Orimo, H. (Ed.), Japan: Univ.・・・
    Kurochkin, I.V., Takahashi, R., Ishigami, A., Fujita, Y. and Goto, S. : Age-related change in the proteolytic activity on the high molecular mass ATP-stimulated protease from mouse liver. In: New Horizons in Aging Science. Orimo, H. (Ed.), Japan: Univ. of Tokyo Press, pp.57-58 (1992)
  • 後藤佐多良、高橋良哉、石神昭人 : 栄養制限下における物質代謝；”環境因子と老化”（松尾光芳 編）学会出版センター， pp.79-95 (1994)

MISC

Industrial Property Rights

Awards & Honors

  • 2020/06 日本ビタミン学会 学会賞
  • 2019/02 日本ビタミン学会 トピックス貢献賞
  • 2006/11 東京都職員表彰（石原慎太郎知事） 知事賞
     JPN
  • 2003/12 生命科学啓明賞
     JPN
  • 2003/11 The 7th Asia/Oceania Regional Congress of Gerontology POSTER AWARD
  • 2003/06 日本老年医学会 ノバルティス老化および老年医学賞
     JPN
  • 2003/05 財団法人 博慈会 老年病研究所 優秀論文賞
     JPN
  • 2003/03 三井住友海上福祉財団 第1回 三井住友海上福祉財団賞
     JPN
  • 2002/05 日本基礎老化学会 若手奨励賞
     JPN

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2026/03 
    Author : 石神 昭人; 橋本 真一
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2025/03 
    Author : 町田 修一; 川西 範明; 石神 昭人
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 千葉 卓哉; 近藤 嘉高; 石神 昭人
  • 日本学術振興会：科学研究費助成事業 基盤研究(B)
    Date (from‐to) : 2019/04 -2022/03 
    Author : 石神 昭人; 橋本 真一
     
    若齢動物の組織には、細胞機能に異常のない「若い細胞」のみが存在する。一方、老齢動物の組織には、細胞機能が衰退、異常化した「老化細胞」が存在し、その数も加齢に伴い増加することが予想される。本研究では、シングルセル(1細胞)遺伝子発現解析(Nx1-seq)により、老化に関連した遺伝子をシングルセルレベルで包括的に探索、同定する。 シングルセル遺伝子発現解析による、老化関連遺伝子の探索研究は順調に進行している。私たちが用いている「老化関連遺伝子」とは、必ずしも老化を制御するなど、老化機構に直接関与する遺伝子を意味するのではなく、加齢による二次的、および三次的に変動する遺伝子もすべて含む総称として老化関連遺伝子と定義する。令和元年度、老齢(27月齢)と若齢(6月齢)のラット肝臓の実質細胞を用いて、老齢で発現量が大きく変動する遺伝子を探索した。そして、4種類の有力な老化関連遺伝子(AGs: Age-associated genes)に絞り込んだ。これら4種類の老化関連遺伝子について、老化や加齢との関連性を明らかにするため、また異なる動物種でも同様の現象が見られるかを確認するため、解析動物をラットからマウスに変更した。そして、若齢から老齢まで様々な月齢(3, 6, 12, 24, 32-34月齢)のマウス肝臓を用いてqPCRによる遺伝子発現の加齢変化を解析した。そして、最終的に加齢変化を示す3種類の老化関連遺伝子(遺伝子名を明らかにできないためAG-1, AG-2, AG-3と表す)にまで絞り込むことができた。これら3種類の老化関連遺伝子は、今までに老化や加齢との関連性を示す研究報告はない。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2018/04 -2021/03 
    Author : Hamano Yoshitomo
     
    Aberrant production of the anti-neutrophil cytosolic autoantibody (ANCA) causes the ANCA related vasculitis (AAV). To analyze the previously identified QTL on chromosome 1 for production of ANCA, we introduced the QTL to B6/lpr and proved the pathogenic function of the QTL (Autoimmunity 52:208, 2019). We identified two candidate genes for abnormal production of ANCA using the next generation sequencer. One was the structual gene for a proteinase inhibitor and it had non-synonymous polymorphisms. We produced recombinant proteins of wild and variant types to analyze their fuctional changes. Another one was the gene coding membrane surface protein on peripheral blood mononuclear cells. We are going to develop these items into the medication experiment to animal individuals, and the surface character analysis of PBMC in a human AAV case. The results can possibly be the seeds for the development of therapautic medicines.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2015/04 -2019/03 
    Author : Ishigami Akihito
     
    We have identified for the first time citrullinated Alzheimer's disease-related proteins in the brains of Alzheimer's disease patients. We also succeeded in developing clinical laboratory diagnostic reagents that quantify it’s citrullinated proteins. It has potential to be useful as a clinical diagnostic agent for quantifying citrullinated Alzheimer's disease-related proteins. In the future, we will verify the usefulness as an early clinical diagnostic agent for Alzheimer's disease.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2015/04 -2018/03 
    Author : Ishigami Akihito
     
    We established SMP30/αTTP double knockout mice as a novel double-deficient model for both vitamin C and vitamin E. SMP30/αTTP double knockout mice showed impaired cue and context-dependent fear memory if both vitamin C and vitamin E were deficient. Moreover, simultaneous deficiency of vitamin C and E revealed that it affects lipid metabolism in the liver.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2018/03 
    Author : Sato Tadashi; ISHIGAMI Akihito; RENNARD Stephen I.; SUZUKI Yohei; MITSUI Aki
     
    Cigarette smoking is the most important cause of COPD, but the mechanisms of pathogenesis are incompletely defined. We have reported that a specific microRNA, miR-146a, plays a pathogenetic role in the abnormal inflammatory response in COPD. In the current study, we investigated the role of miR-146a in acute phase of inflammatory response towards cigarette smoking. Interleukin-8 was significantly increased in BEAS-2B cells, normal human bronchial epithelial cells, following 6 days of cigarette smoke extract (CSE) and 2 days of lipopolysaccharide (LPS) compared with non-CSE treatment cells (70.2→118.1 pg/mL, P<0.01). Additionally, LPS-induced miR-146a expression was also increased significantly by pretreatment of CSE (relative expression: 44.0→70.1, P<0.01). Together, LPS-induced inflammatory response was clearly enhanced by CSE pretreatment in human bronchial epithelial cells. Moreover, miR-146a may associate with the acute inflammatory response during the exacerbation of COPD.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2018/03 
    Author : Sugihara Takahiko
     
    The patients with elderly-onset rheumatoid arthritis (RA) can achieve clinical remission and normal physical function by therapeutic strategy targeting low disease activity(T2T). Anti-cyclic citrullinated peptide antibody, bone erosion, high disease activity, and clinical responses at initial treatment are predictors of joint destruction. Serious adverse events under T2T strategy of EORA have great impact on physical dysfunction in patients who achieved treatment goals. Peptidylarginine Deiminase 4 (PAD4) protein expression in peripheral blood is not associated with disease activity. Genome-wide association studies (GWAS) have identified new single nucleotide polymorphisms (SNPs) related to susceptibility of RA. However the SNP cannot predict treatment response of EORA in our prospective cohort. We would like to establish T2T strategy cooperated with SNP related to treatment response and adverse events, but not RA susceptibility.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : Maruoka Hiroshi; Ishigami Akihito; Kanemura Naohiko; Tanaka Kenichi; Matumoto Jyunichi
     
    This study examined the influences of exercise after right femoral arterial ligation on pro-angiogenic factors. Wild-type or Vitamin C knock-out mice were randomized groups (based on the presence/absence of ligation). The oxidative stress level was significantly higher at 1 W and 3 W in the compared to Sham group. HIF-1α values were significantly higher at 3 W in the and compared to Sham group. The values representing the pro-angiogenic factors PGC-1α and IL-6 were significantly higher and those representing the anti-angiogenic factor endostatin were markedly lower in the compared to Sham group. In a mice model of lower-limb ischemia, changes in the oxidative stress level were observed from 1 W. An increased HIF-1α level was also observed at 3 W. In this study, the balance between pro- and anti-angiogenic factors was clarified during a 6-weeks exercise program.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : Matsumoto Shigekiyo; KOGA Hironori; ISHIGAMI Akihito
     
    Senescence marker protein-30 (SMP30) / gluconolactonase (GNL) knockout (KO) mice were divided into vitamin C (VC) (+) or VC (-). VC (+) mice were given water containing 1.5 g/L ascorbic acid (AA), whereas VC (-) mice received water without AA. Mice were intraperitoneally injected with lethal dose of lipopolysaccharide (LPS) evaluated physiological parameters and liver and lung injury at 3h after LPS. These results show no significant differences both groups. We speculate that sacrifices after LPS may be too early. Currently SMP30/ GNL KO mice are receiving water without AA and will become VC (-) mice in October of this year. In next study, high dose of AA or saline will be intraperitoneally administered to VC (-) mice 30 min before lethal dose of LPS injection. At 6-12h after LPS, pituitary-adrenal hormones, oxidative stress markers, inflammatory markers and various organ injuries are going to be measured and evaluated.
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2014/04 -2016/03 
    Author : 加賀美 弥生; 石神 昭人
     
    翻訳後修飾の一つであるタンパク質シトルリン化は、生理的及び疾患病理的側面を有する事象である。アルツハイマー型認知症（AD）患者の脳では、シトルリン化タンパク質が検出される。本研究では、シトルリン化タンパク質の神経細胞への影響やAD脳におけるシトルリン化タンパク質の局在性、AD患者のシトルリン化タンパク質に対する自己抗体産生の有無などを検討し、タンパク質シトルリン化とADとの関連について解析することを目的とした。 シトルリン化酵素であるPAD2を用いて、シトルリン化タンパク質を作製した。また、合成シトルリン化タンパク質をマウスに免疫し、シトルリン化タンパク質特異的に反応するモノクローナル抗体を得た。シトルリン化タンパク質と抗体を用いて、シトルリン化タンパク質に対する自己抗体検出用のELISAシステムの構築を試みている。 シトルリン化タンパク質が神経細胞に与える影響をラット胎仔由来の初代培養細胞を用いて解析した。その結果、シトルリン化タンパク質により細胞生存率は低下しなかった。タンパク質シトルリン化の生理的役割やADの発症や進行を明らかにする上で有用な知見が得られた。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : SUZUKI Hideharu; ISHIGAMI Akihito
     
    We thought aggregation inhibitor of amyloid beta would be a prophylactic agent for Alzheimer diseases, furthermore disrupting compound for the aggregation, it would be a therapeutic medication. To inhibit Amyloid-β (Aβ) aggregation/fibril formation, we have found a concept that an Aβ-recognition compound attached to the hydrophilic moiety act as a strong Aβ-aggregation inhibitor. Many phenolic derivatives of 2, 5-diarylbenzofuran are synthesized according to our concept. Some poly-hydric phenol derivatives showed strong activities for Aβ aggregation and fibril formation inhibitory activity and dissociation activity for Aβ fibrils and aggregates. These activities are obviously related to the number of hydroxyl groups in the structures. Viewing from the Log P values of structures, the compounds having around Log P=4 values are showed the most strong activities. From the molecular weight and Log P values, these strong inhibitors would be expected to cross the BBB.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : TAKEISHI Yasuchika; OIKAWA Masayoshi; SUZUKI Satoshi; ISHIGAMI Akihito
     
    Doxorubicin was administerd to wild type mice, SMP30 knockout mice, and transgenic mice with cardiac specific overexpression of SMP30. We demonstrated that SMP30 has a cardio-protective role by anti-oxidative and anti-apoptotic effects in doxorubicin-induced cardiotoxicity. Anti-aging gene, SMP30, can be a new therapeutic target to prevent heart failure.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : ISHIGAMI Akihito
     
    Peptidylarginine deiminases (PADs) are post-translational modification enzymes that citrullinate protein arginine residues. Abnormal protein citrullination by PAD2 has been closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). In this study, we tried to develop a novel method for sandwich enzyme-linked immunosorbent assay (ELISA) for the determination of citrullinated proteins which may become a useful marker of human neurodegenerative diseases.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2012/04 -2015/03 
    Author : ISHIGAMI Akihito
     
    We investigated the impact of maternal vitamin C (VC) content on the growth of fetal mice during the gestation period by using senescence marker protein-30 (SMP30) /gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize VC in vivo. As a results, a diet sufficiently replete with VC is essential during the gestational period for normal tissue development in the fetus and neonate. Moreover, we investigated whether VC-treatment not only prevents but restores smoke-induced emphysema in SMP30/GNL KO mice. As a results, we found that VC-treatment may provide a new therapeutic strategy for chronic obstructive pulmonary disease (COPD) in human.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : HASEGAWA Goji; ISHIGAMI Akihito; FUKUI Michiaki; YAMAZAKI Masahiro
     
    Senescence marker protein-30 (SMP30) decreases with age and contributes to the symptoms of aging. In this study, we investigated the effect of SMP30 deficiency on the pathogenesis of diabetic nephropathy using streptozocin induced diabetic SMP30 knockout (KO) mice. Tubular damages with tubulointerstitial fibrosis were observed in non-diabetic KO mice, and diabetes exacerbated these changes. On the other hand, SMP30 deletion did not affect glomerular changes. The accumulation of HIF-1alpha, the increase of oxidative stress, and tubular inflammation were associated with tubular injuries. In conclusion, decreased SMP30 with age may contribute to the progression of diabetic nephropathy through tubular damages.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2009 -2011 
    Author : HANDA Setsuko; ISHIGAMI Akihito
     
    The abnormal accumulation of citrullinated proteins were detected in the brain from Alzheimer's disease(AD) patients. By using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, two of the citrullinated proteins were identified as a vimentin and a glial fibrillary acidic protein(GFAP). In addition, we constructed a ELISA system which detect the citrullinated GFAP to develop diagnostic laboratory tests for early diagnosis of AD.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2009 -2011 
    Author : TAKEISHI Yasuchika; SAITOH Shu-ichi; ISHIGAMI Akihito
     
    In SMP30 knockout mice, cardiac function was more severely depressed after angiotensin II infusion compared to wild type mice. Angiotensin IIinduced increases in NADPH oxidase activity, ROS generation, c-Jun N terminal kinase activity, a ratio of Bax/Bcl, caspase activity, and numbers of TUNEL positive nuclei were greater in SMP30 knockout mice. Thus, SMP30 may have cardio-protective roles by antioxidant and anti-apoptotic effects.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2009 -2011 
    Author : ISHIGAMI Akihito; HANDA Setsuko
     
    We examined the effect of vitamin C depletion in lung from vitamin C depleted SMP30/GNL knockout mice by histopathologic and morphologic evaluations. Our results suggest that vitamin C protects lungs from oxidative stress and age-related lung diseases including cigarette smoke-induced chronic obstructive pulmonary disease(COPD).
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2008 -2010 
    Author : HASEGAWA Goji; ISHIGAMI Akihito
     
    The impairment of early phase of insulin secretion due to dysfunction of the distal portion of insulin secretion pathway underlies glucose intolerance in SMP30 knockout mice. Decreased SMP30 may contribute to the worsening of glucose tolerance that occurs in normal aging.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2007 -2008 
    Author : HANDA Setsuko
     
    カルニチンはβ酸化によりエネルギー(ATP)を得るため脂肪酸を細胞質からミトコンドリア内に運ぶ重要な因子である。カルニチンはタンパク質中のリシンとメチオニンから生合成されるが、この時ビタミンCが必須といわれている。本研究では、生体内でのカルニチン合成にビタミンCが必須であるか明らかにするため、ビタミンCを体内で合成できない遺伝子破壊(SMP30/GNL-KO)マウスを用いて実験を行った。このマウスを用いたin vivoおよびin vitro実験からビタミンCが生体内のカルニチン生合成系に必須でないことが明らかになった。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2007 -2008 
    Author : KUBO Sachiho
     
    世界に先駆けてその作成に成功したウサギ疾患モデルとマウスを使い、抗MuSK 抗体陽性重症筋無力症の病態解明と治療法の開発を可能とした(Ann N Y Acad Sci. 2008).ウサギ疾患モデルの神経筋シナプスの形態変化を共焦点顕微鏡と透過型電子顕微鏡で詳細に明らかにした. 発症したウサギの神経筋シナプス全体の形態変化が観察され、自己抗体がMuSK によるシナプスの維持機構を阻害することで発症することが明らかとなった.またウサギモデルの血清に存在する抗MuSK 抗体は、一価の抗原結合部位しかないにも関わらずMuSK の機能を抑制する. 発症したウサギのシナプス後膜に補体による破壊像が観察されない結果とあわせて、重症筋無力症が補体の関与がなくても発症することが明らかとなった. さらに、我々は抗MusK 抗体陽性患者の病態により近い疾患動物モデルの作成に成功した. 患者の血清に含まれる抗MuSK 抗体のIgG のサブクラスは補体結合が欠如するタイプ4 が大半を占めている.我々は補体欠損マウスに、抗MuSK抗体で重症筋無力症を発症させることに成功した.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2007 -2008 
    Author : SHIMADA Nobuko
     
    慢性閉塞性肺疾患(COPD)は喫煙が主な原因とされる肺の生活習慣病である。COPD発症要因のひとつは肺での酸化ストレスの増加と考えられている。そこで本研究では、ビタミンCを合成できない遺伝子破壊マウス(SMP30/GNLノックアウトマウスを用いて、ビタミンC不足が肺に与える影響を検討した。その結果、ビタミンC不足は肺における酸化ストレスの増大や肺胞径、肺胞破壊の増大を招くことが明らかになった。ビタミンCの不足はCOPD発症リスクを高めると考えられる。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2007 
    Author : ISHIGAMI Akihito; HANDA Setsuko
     
    Citrullinated proteins are the products of a post-translational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. In mammalian tissues, PADs are found as five different isoforms (i.e, types 1-4, 6). PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of the citrullination in neuronal degeneration, we examined whether citrullinated proteins are produced in Alzheimer's disease (AD), Parkinson's disease, and Huntington chorea. 1. Histochemical analysis revealed that citrullinated proteins were detected all over the hippocampus. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also detected all over the hippocampus both in the AD and the normal brain. Double immunofluorescence staining revealed that citrullinated protein-and PAD2-positive cells were well coincidenced with GFAP-positive cells, but not all GFAP-positive cells were PAD2-positive cells. As GFAP is a astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. 2. Citrullinated proteins with various molecular weight were detected in AD hippocampus by Western blot analysis, but not in normal brain. Two of the citrullinated proteins were identified as a vimentin and a glial fibrillary acidic protein (GFAP). Thus, abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 is occurring in AD hippocampus. These results strongly suggested that PAD has an important role in the onset and progression of AD and citrullinated proteins may became a possible useful marker for human neurodegenerative disease.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2005 -2006 
    Author : KUBO Sachiho; MARUYAMA Naoki; ISHIGAMI Akihito
     
    Citrullinated proteins are the products of a post-translational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner. In our previous report, PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of protein citrullination in human neuronal degeneration, we examined whether citrullinated proteins are produced during Alzheimer's disease (AD). By Western blot analysis using anti-modified citrulline antibody, citrullinated proteins of varied molecular weights were detected in hippocampal tissues from patients with AD but not normal humans. Two of the citrullinated proteins were identified as vimentin and glial fibrillary acidic protein (GFAP) by using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Interestingly, PAD2 was detected in hippocampal extracts from AD and normal brains, but the amount of PAD2 in the AD tissue was markedly greater. Histochemical analysis revealed citrullinated proteins throughout the hippocampus, especially in the dentate gyrus and stratum radiatum of CA1 and CA2 areas. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also ubiquitous throughout both the AD and normal hippocampal areas. PAD2-enrichment coincided well with citrullinated protein-positivity. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells also coincided with GFAP-positive cells, but not all GFAP-positive cells were positive for PAD2. Like GFAP, which is an astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. These collective results, the abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 in hippocampi of patients with AD, strongly suggest that PAD has an important role in the onset and progression of AD and that citrullinated proteins may became a useful marker for human neurodegenerative diseases.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2003 -2005 
    Author : HANDA Setsuko; MARUYAMA Naoki; ISHIGAMI Akihiko
     
    Senescence marker protein-30 (SMP30) is a 34-kDa protein whose tissue levels in the liver, kidney, and lung decrease with aging. To elucidate the physiological role of this protein, we introduced a null mutation of the SMP30 gene into the germ line of mice, and then investigated the tissue susceptibility for apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) using primary cultured hepatocytes. Consequently, cells that are completely lacking SMP30 (SMP30-/-) were more susceptible to apoptosis induced by TNF-alpha plus actinomycin D (Act-D) than SMP30+/+ hepatocytes, indicating that SMP30 can protect cells from apoptosis induced by TNF-alpha plus Act-D. However, the responsible mechanism(s) for anti-apoptotic effect of SMP30 has not been fully understood. Therefore we aimed in this study that the elucidation of the apoptosis inhibitory action of SMP30. Human hepatocellular carcinoma cell line was transfected with pcDNA3/SMP30 (SMP30 transfectants), or as a control with pcDNA3 (mock transfectants). When cells were exposed to 20 ng/ml tumor necrosis factor-alpha (TNF-alpha) plus 10 ng/ml actinomycin D (Act-D) for 15 h, the viability of cells was decreased in both SMP30 and mock transfectants. However, the viability of cells was threefold higher in SMP30 transfectants than mock transfectants. Cell death was confirmed as apoptosis by TUNEL assay. The presence of trifluoperazine, a calmodulin (CaM) inhibitor, attenuated anti-apoptotic effect of SMP30 in both transfectants, but the effect was more prominent in SMP30 transfectants. Western blot analyses revealed that Akt, which acts as a survival factor in cells, was activated in SMP30, but not mock, transfectants either in the presence or absence of TNF-alpha plus Act-D. Further, trifluoperazine inhibited Akt activation in SMP30 transfectants. We therefore propose that interplay between CaM and SMP30 regulates Akt activity, and thus SMP30 acts as a survival factor in hepatocytes.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2002 -2004 
    Author : ISHIGAMI Akihito; MARUYAMA Naoki; HANDA Setsuko
     
    Citrullinated proteins are the products of a post-translational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases(PADs) in a calcium ion-dependent manner. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. In mammalian tissues, PADs are found as five different isoforms (i.e, types 1-4,6). PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of the citrullination in neuronal degeneration, we examined whether citrullinated proteins are produced in Alzheimer's disease(AD), Parkinson's disease, and Huntington chorea. 1.Histochemical analysis revealed that citrullinated proteins were detected all over the hippocampus. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also detected all over the hippocampus both in the AD and the normal brain. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells were well-coinddenced with GFAP-positive cells, but not all GFAP-positive cells were PAD2-positive cells. As GFAP is a astrocyte-spedfic marker protein, PAD2 is distributed mainly in astrocytes. 2.Citrullinated proteins with various molecular weight were detected in AD hippocampus by Western blot analysis, but not in normal brain. Two of the citrullinated proteins were identified as a vimentin and a glial fibrillary acidic protein(GFAP). Thus, abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 is occurring in AD hippocampus. These results strongly suggested that PAD has an important role in the onset and progression of AD and citrullinated proteins may became a possible useful marker for human neurodegenerative disease.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1995 -1996 
    Author : SENSHU Tatsuo; OHSAWA Takako; ISHIGAMI Akihito; ASAGA Hiroaki; AKIYAMA Kyoichi
     
    We previously reported the presence of deiminated keratins and filaggrin in rat epidermis (J.Invest. Dermtol. 105,163-69 (1995) ; supported by Grant-in-Aide 06833012). Here we performed identification of the major deiminated keratin molecule and cloning of peptidylarginine deiminase (PAD) cDNAs. We also conducted comparative studies of protein deimination using various experimental systems. 1. Major deiminated proteins in human and mouse epidermis were identified to be partially degraded and disulfide-cross-linked keratin K1 in the cornified layr suggesting the possible role of protein deimination in modulating the interaction of K1 with its partner keratin K10, pre-existent keratins K5/K14 network or keratin-associated proteins. 2. Three PAD clones were isolated from a cDNA library of immortalized newbom rat kerationcytes that had been induced to express PAD with retinoic acid. One of them closely resembled skeletal muscle PAD cDNA previously obtained in our laboratory. The other two appeared to be novel cDNAs encoding PADs. Further research is in progress to see if either of them encodes PAD expressed in the epidermis. 3. Deimination of keratins and filaggrin in mouse epidermis was found to increase markedly during postnatal few hours. Cultivation of late prenatal embryonic skin suggested that exposure to air is required for normal deimination of these epidermal proteins. Comparative studies using human, rat, mouse, and guine a pig showed significant species differences in filaggrin deimination.
  • 日本学術振興会：科学研究費助成事業 一般研究(C)
    Date (from‐to) : 1994 -1994 
    Author : 千秋 達雄; 秋山 翹一; 石神 昭人
     
    タンパク質の脱イミノ化が、表皮の角化と関わることを想定し、以下の研究を実施した。 ラット表皮に存在する脱イミノ化タンパク質の性質と組織内局在:ラット表皮から変性条件で可溶化したタンパク質区分を、ゲル電気泳動で分別後、全タンパク質を銀染色法により、脱イミノ化タンパク質、ケラチン、フィラグリンはウエスタン法により検出し、脱イミノ化タンパク質の同定を行った。発達した成獣足裏角層には68-70Kケラチンの脱イミノ化が、やや未発達の幼若ラット角層では60Kケラチンの脱イミノ化が夫々顕著に見られた。体毛の密生した成獣体表の角層には脱イミノ化ケラチンは存在せず、混入する毛根由来のトリコヒアリンの脱イミノ化産物が見られた。また、幼若ラット全表皮では、微量ながらフィラグリンの脱イミノ化物が認められた。免疫細胞化学的には、脱イミノ化タンパク質は角層、特にその下部に多く認められた。 培養細胞系における脱イミノ化タンパク質の動態:不死化したラット新生児表皮培養細胞系では、集密状態に達してのち既知の角化マーカータンパク質の出現と前後して脱イミノ化タンパク質の蓄積開始が見られた。培養条件下で、脱イミノ化反応を触媒するペプチジルアルギニンデイミナーゼ生合成の誘導条件を見出したので、精製法の検討を進めている。 ヒト表皮における脱イミノ化タンパク質の動態:粘着テープで段階的に剥離したヒト表皮のタンパク質を分析した。顆粒層でフィラグリン、角層でケラチンの優先的脱イミノ化が見られた。免疫細胞化学的に、脱イミノ化タンパク質はフィラグリンと同様、顆粒層に多く認められた。
  • Functional analysis of peptidylarginine deiminase (PAD)
  • Citrullinated protein and Alzheimer's disease
  • Senescence marker protein-30 (SMP30) and age-associated organ disorders
  • Biomarkers of aging and their clinical applications
  • Vitamin C and aging

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