Development of preventive markers for cerebrovascular disease using novel oxidized modification products of proteins

• Project/Area Number: 26350907
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: Yamakura Fumiyuki 順天堂大学, 国際教養学部, 特任教授 (20053358)
• Co-Investigator(Kenkyū-buntansha): 川崎 広明 順天堂大学, 医学(系)研究科(研究院), 特任研究員 (40531380) ; 飯泉 恭一 順天堂大学, スポーツ健康科学部, 助手 (30439351)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ニトロトリプトファン / 酸化傷害 / 脳卒中易発性高血圧発症ラット / アポリポプロテインＥ / arginosuccinate synthase / アポリポプロテインE / コレステロール / ニトロ化ストレス / 脳卒中易発性自然発症高血圧ラット / SHR-SP / 肝臓 / アポＥタンパク質 / SHR

Outline of Final Research Achievements

Oxidative stress is known to participate for development of cardiovascular diseases. We have developed a new marker for oxidative stress, which is 6-nitrotryptophan (NO2Trp). We have applied this method for stroke-prone spontaneously hypertensive rat, SHRSP.　We have found NO2Trp in apolipoprotein E (ApoE), in serum from SHRSP at 18 weeks of age, just before onset of the stroke. In order to clarify the relation between tissue injury and NO2Trp in ApoE, we have checked heart, brain, liver, and kidney of the SHRSP. However, we could not observed NO2Trp in ApoE in each of the tissues.　Instead, we observed four other proteins in heart, 5 other proteins in brain, 10 other proteins in liver as NO2Trp containing proteins. Among them, arginosuccinate synthase in liver is important, because this enzyme is known to control formation of nitric oxide, an important regulator of hypertension. Therefore, nitration of this enzyme may participate formation of hypertension, at least partly, in SHRSP.

Research Products

• [Int'l Joint Research] The Heart Research Institute, Sydney(オーストラリア)
• [Journal Article] Accumulation of immunoglobulin G against Dermatophagoides farinae tropomyosin in dorsal root ganglia of NC/Nga mice with atopic dermatitis-like symptoms. (2017)
  • Author(s): Otsu A, Kawasaki H, Tominaga M, Shigenaga A, Matsuda H, Takahashi N, Nakajima T, Naito H, Baba T, Ogawa H, Tomooka Y, Yamakura F, Takamori K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 485 Issue: 4 Pages: 707-712
  • DOI: 10.1016/j.bbrc.2017.02.109
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Peroxynitrite-mediated oxidation of plasma fibronectin (2016)
  • Author(s): Degendorfer G, Chuang CY, Kawasaki H, Hammer A, Malle E, Yamakura F, Davies MJ.
  • Journal Title: Free Radic. Biol Med Volume: 97 Pages: 602-615
  • DOI: 10.1016/j.freeradbiomed.2016.06.013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Electrophysiological properties of brain-natriuretic peptide- and gastrin-releasing peptide-responsive dorsal horn neurons in spinal itch transmission. (2016)
  • Author(s): Kusube F ,Tominaga M, Kawasaki H, Yamakura F, Naito H, Ogawa H, Tomooka Y, Takamori K,
  • Journal Title: Neuroscience Letters Volume: 627 Pages: 51-60
  • DOI: 10.1016/j.neulet.2016.05.051
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bioinformatic identification of cytochrome b5 homologues from the parasitic nematode Ascaris suum and the free-living nematode Caenorhabditis elegans highlights the crucial role of A. suum adult-specific secretory cytochrome b5 in parasitic adaptation. (2015)
  • Author(s): Takamiya S, Hashimoto M, Mita T, Yokota T, Nakajima Y, Yamakura F, Sugio S,
  • Journal Title: Parasitol Int. Volume: 65 Issue: 2 Pages: 113-20
  • DOI: 10.1016/j.parint.2015.11.004
  • Peer Reviewed
• [Journal Article] Sumoylated α-skeletal muscle actin in the skeletal muscle of adult rats. (2015)
  • Author(s): Munehiro Uda、Hiroaki Kawasaki、Kyoichi Iizumi、Ayako Shigenaga、Takeshi Baba、Hisashi Naito、Toshitada Yoshioka 、Fumiyuki Yamakura
  • Journal Title: Molecular and Cellular Biochemistry Volume: 409 Issue: 1-2 Pages: 59-66
  • DOI: 10.1007/s11010-015-2512-1
  • Peer Reviewed / Open Access
• [Journal Article] Importance of the tryptophan nitration of carbonic anhydrase III for the morbidity of atopic dermatitis (2014)
  • Author(s): Hiroaki Kawasaki, Mitsutoshi Tominaga, Ayako Shigenaga, Atsuko Kamo, Yayoi Kamata, Kyoichi Iizumi, Utako Kimura, Hideoki Ogawa, Kenji Takamori, Fumiyuki Yamakura
  • Journal Title: Free Radic Biol Med Volume: 73 Pages: 75-83
  • DOI: 10.1016/j.freeradbiomed.2014.04.034
  • Peer Reviewed
• [Journal Article] Effect of substituting Trp for Leu t position 72 on the structure of Porphyromonas gingivalis superoxide dismutase (2014)
  • Author(s): Komachiya M, Mizoue S, Mihara M, Osawa M, Kikuchi Y, Uematsu S, HIrai K, Okubo Y, Kuroiwa A, Yamada K, Yamakura F, Hiraoka B Y
  • Journal Title: Matsumoto Shigaku Volume: 40 Pages: 19-25
  • Peer Reviewed
• [Journal Article] Contribution of the amino acid resudues located near the active site metal to the metal-specific activity of Porphyromonas gingivalis SOD induced by a double mutation of Leu72Trp and Leu76Phe (2014)
  • Author(s): Mihara M, Komachiya M, Mizoue S, Osawa M, Uematsu S, Kikuchi Y, Okubo Y, Hirai K, Kuroiwa A, Yamada K, Yaakura F, Hiraoka BY,
  • Journal Title: Matsumoto Shigaku Volume: 40 Pages: 26-34
  • Peer Reviewed
• [Presentation] Localization of IgG against Dermatophagoides farina-tropomyosin in dorsal root ganglia of NC/Nga mice with atopic dermatitis-like symptoms (2016)
  • Author(s): Ayaka Otsu, Hiroaki Kawasaki, Mitsutoshi Tominaga, Ayako Shigenaga, Kyoichi Iizumi, Takeshi Baba, Hisashi Naito, Hideoki Ogawa, Tadaaki Nakajima, Yasuhiro Tomooka2 Fumiyuki Yamakura, Kenji Takamori
  • Organizer: 第４１回日本研究皮膚科学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-12-09
• [Presentation] 6-ニトロトリプトファン生成によCarbonic anhydrase IIIの機能傷害とアトピー性皮膚炎病態形成 (2016)
  • Author(s): 川崎広明、冨永光俊、松本綾子、飯泉恭一、馬場猛、大津彩夏、 楠部史也、池田啓一、髙森建二、山倉文
  • Organizer: 第３７回日本トリプトファン研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-09
• [Presentation] 6－ニトロトリプトファンを指標としたアトピー性皮膚炎の早期検出 (2016)
  • Author(s): 飯泉恭一、川崎広明、冨永光俊、重永綾子、加茂敦子、鎌田弥生、髙森建二、山倉文幸
  • Organizer: 第３７回日本トリプトファン研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-09
• [Presentation] ペルオキシナイトライト修飾によるトリプシン及びキモトリプシンの酵素活性への影響, (2016)
  • Author(s): 須藤絢音、池田啓一、重永綾子、川崎広明、興村桂子、小林淳、渡辺和人、酒口久尚、山倉文幸,
  • Organizer: 日本生化学会、第89回大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] Identification of 6-NO2Trp containing proteins in SHRSP-possible relation to hypertension (2016)
  • Author(s): Kawasaki H, Ikeda M, Sakai K, Matsumoto M, Iizumi K, Baba T, KTakamori K, Yamakura F
  • Organizer: The16th International Union of Biochemistry and Molecular Biology Conference
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-07-17
  • Int'l Joint Research
• [Presentation] Studies on a novel biomarker for atopic dermatitis (2016)
  • Author(s): ) Iizumi K, Kawasaki H, Tominaga M, Shigenaga A, Kamo A, Kamata Y, Takamori K, Yamakura F
  • Organizer: The16th International Union of Biochemistry and Molecular Biology Conference,
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-07-17
  • Int'l Joint Research
• [Presentation] ニトロ化ストレスとかゆみ〰アトピー性皮膚炎とニトロ化タンパク質 (2015)
  • Author(s): 川崎広明、山倉文幸
  • Organizer: 順天堂大学大学院医学研究科環境医学研究所 文部科学省平成25年度私立大学戦略的研究 基盤 形成支援事業 第2回公開シンポジュム
  • Place of Presentation: 本郷 東京
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] 骨格筋で新たに見出された分子量の異なるa-アクチン の細胞内局在の検討 (2015)
  • Author(s): 宇田宗弘、川崎広明、飯泉恭一、重永綾子、馬場猛、内藤久士、 吉岡利忠、山倉文幸
  • Organizer: 第７０回日本体力医学会
  • Place of Presentation: 和歌山県
  • Year and Date: 2015-09-18
• [Presentation] Nitration of tryptophan residues in proteins: Important roles in some diseases (2015)
  • Author(s): Yamakura F
  • Organizer: International Society For Tryptophan Research Conference
  • Place of Presentation: Grand Rapids, MI, USA
  • Year and Date: 2015-09-16
  • Int'l Joint Research / Invited
• [Presentation] 型糖尿病モデルマウスでのトリプトファンニトロ化による Glutathione s-transferaseの機能障害 (2015)
  • Author(s): 川崎広明、馬場猛、重永綾子、飯泉恭一、髙森建二、山倉文幸
  • Organizer: 第１５回日本ＮＯ学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター、大阪
  • Year and Date: 2015-06-26
• [Presentation] ６－ニトロトリプトファン修飾免疫グロブリンはアトピー性 皮膚炎のマーカーになり得るか？ (2015)
  • Author(s): 飯泉恭一、冨永光俊、川崎広明、重永綾子、加茂敦子、鎌田弥生、 髙森建二、山倉文幸
  • Organizer: 第１５回日本ＮＯ学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター、大阪
  • Year and Date: 2015-06-26
• [Presentation] ６－ニトロトリプトファンの血漿バイオマーカーとしての可能性－アトピー性皮膚炎 (2014)
  • Author(s): 飯泉恭一、冨永光俊、川崎広明、重永綾子、加茂敦子、鎌田弥生、髙森建二、山倉文幸
  • Organizer: 第３６回日本トリプトファン研究会学術集会
  • Place of Presentation: 旭川医科大学
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] ２型糖尿病モデルマウスにおける６－ニトロトリプトファンの生体内生成 (2014)
  • Author(s): 川崎広明、馬場猛、松本綾子、飯泉恭一、池田啓一、髙森建二、山倉文幸
  • Organizer: 第３６回日本トリプトファン研究会学術集会
  • Place of Presentation: 旭川医科大学
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] 骨格筋α－アクチンの新規翻訳後修飾 (2014)
  • Author(s): 田宗弘、川崎広明、飯泉恭一、重永綾子、馬場猛、内藤久士、山倉文幸
  • Organizer: 第６９回日本体力医学会
  • Place of Presentation: 長崎大学文教キャンパス
  • Year and Date: 2014-09-19 – 2014-09-21
• [Presentation] 脳卒中易発性高血圧自然発症ラットSHR-SPでの6-ニトロトリプトファン生成 ～タンパク質機能傷害と病態形成の関連性の解明～ (2014)
  • Author(s): 川崎広明、池田雅彦、酒居一雄、重永綾子、飯泉恭一、宇田宗弘、馬場猛、髙森建二、山倉文幸
  • Organizer: 第1４回日本NO学会学術集会
  • Place of Presentation: ホテルニューオータニ佐賀
  • Year and Date: 2014-05-16 – 2014-05-17