Development of atropine esterase formulation to improve the effect of atropine used in the anesthesiology field

• Project/Area Number: 19K09408
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Satoru Yamazaki 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70348796)
• Co-Investigator(Kenkyū-buntansha): 北風 政史 国立研究開発法人国立循環器病研究センター, 病院, 客員研究員 (20294069) ; 塚本 蔵 大阪大学, 生命機能研究科, 准教授 (80589151) ; 中谷 明弘 東京大学, 大学院新領域創成科学研究科, 特任教授 (60301149)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アセチルコリン受容体拮抗薬 / アトロピン / 迷走神経緊張 / 麻酔覚醒 / 洞性徐脈 / 瞳孔拡張 / 自然淘汰 / アセチルコリン受容体拮抗薬アトロ ピン / アセチルコリン受容体拮抗薬アトロ

Outline of Research at the Start

救急医療においてアセチルコリン受容体拮抗薬であるアトロピンは、麻酔からの覚醒、心筋梗塞における洞性徐脈からの回復、あるいは眼科領域における瞳孔散大による診断などの目的で広く使用されている。しかしながら、ヒトにおいてはアトロピンを代謝する機構がないため、その副作用を防ぐには効果的にリバースする製剤の開発が望まれる。
それゆえ、本研究では、ウサギに存在することが予想されるアトロピンエステーゼの分子実態を、生化学およびゲノム・遺伝学的アプローチを用いて明らかにし、最終的にはアトロピンエスラーゼ製剤開発への橋渡しを行うものである。

Outline of Final Research Achievements

In emergency medicine, atropine is widely used for the purpose of awakening from anesthesia and recovery from sinus bradycardia in myocardial infarction. However, since there is no mechanism for metabolizing atropine in humans, it is desired to develop a drug that effectively reverses it in order to prevent side effects. Therefore, we attempted to isolate atropine esterase from rabbits with evidence of atropine esterase. It was one of the results that the mutant form of ACh-induced potassium channel in bradycardic arrhythmia was found to be atropine-sensitive, and as a result, the gene was not isolated.

Academic Significance and Societal Importance of the Research Achievements

これまでに未解明であったアトロピンエステラーゼの実態を明らかにできることが、本研究にまず期待されることであった。しかしながら、本申請ではアトロピンエステラーゼの単離は成功しなかった。アトロピンエステラーゼの実態が明らかになれば、救急医療におけるアトロピン拮抗剤の開発に将来的につながる可能性があるので、今後もその方向での研究が期待される

Research Products

• [Journal Article] Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes (2022)
  • Author(s): Inoue Hiroyuki、Nakamura Satoki、Higo Shuichiro、Shiba Mikio、Kohama Yasuaki、Kondo Takumi、Kameda Satoshi、Tabata Tomoka、Okuno Shota、Ikeda Yoshihiko、Li Junjun、Liu Li、Yamazaki Satoru、Takeda Maki、Ito Emiko、Takashima Seiji、Miyagawa Shigeru、Sawa Yoshiki、Hikoso Shungo、Sakata Yasushi
  • Journal Title: Stem Cell Reports Volume: 17 Issue: 2 Pages: 337-351
  • DOI: 10.1016/j.stemcr.2021.12.016
  • Peer Reviewed / Open Access
• [Journal Article] ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis (2021)
  • Author(s): Min Kyung-Duk、Asakura Masanori、Shirai Manabu、Yamazaki Satoru、Ito Shin、Fu Hai Ying、Asanuma Hiroshi、Asano Yoshihiro、Minamino Tetsuo、Takashima Seiji、Kitakaze Masafumi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 23056-23056
  • DOI: 10.1038/s41598-021-02390-0
  • Peer Reviewed / Open Access
• [Journal Article] AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP‐170 (2020)
  • Author(s): Yashirogi Shohei、Nagao Takemasa、Nishida Yuya、Takahashi Yusuke、Qaqorh Tasneem、Yazawa Issei、Katayama Toru、Kioka Hidetaka、Matsui Tsubasa S、Saito Shigeyoshi、Masumura Yuki、Tsukamoto Osamu、Kato Hisakazu、Ueda Hiromichi、Yamaguchi Osamu、Yashiro Kenta、Yamazaki Satoru、Takashima Seiji、Shintani Yasunori
  • Journal Title: EMBO reports Volume: 22 Issue: 1
  • DOI: 10.15252/embr.202050949
  • Peer Reviewed / Open Access
• [Journal Article] In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance (2020)
  • Author(s): Kioka Hidetaka、Kato Hisakazu、Fujita Takeshi、Asano Yoshihiro、Shintani Yasunori、Yamazaki Satoru、Tsukamoto Osamu、Imamura Hiromi、Kogo Mikihiko、Kitakaze Masafumi、Sakata Yasushi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 2 Pages: 2041-2054
  • DOI: 10.1096/fj.201901686r
  • Peer Reviewed
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Population genetics: past, present, and future (2020)
  • Author(s): Okazaki Atsuko、Yamazaki Satoru、Inoue Ituro、Ott Jurg
  • Journal Title: Human Genetics Volume: 140 Issue: 2 Pages: 231-240
  • DOI: 10.1007/s00439-020-02208-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Higd1a improves respiratory function in the models of mitochondrial disorder (2019)
  • Author(s): Nagao Takemasa、Shintani Yasunori、Hayashi Takaharu、Kioka Hidetaka、Kato Hisakazu、Nishida Yuya、Yamazaki Satoru、Tsukamoto Osamu、Yashirogi Shohei、Yazawa Issei、Asano Yoshihiro、Shinzawa‐Itoh Kyoko、Imamura Hiromi、Suzuki Takeo、Suzuki Tsutomu、Goto Yu‐ichi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 1859-1871
  • DOI: 10.1096/fj.201800389r
  • Peer Reviewed
• [Journal Article] A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 2 (2019)
  • Author(s): Kamikubo Kenta、Kato Hisakazu、Kioka Hidetaka、Yamazaki Satoru、Tsukamoto Osamu、Nishida Yuya、Asano Yoshihiro、Imamura Hiromi、Kawahara Hiroyuki、Shintani Yasunori、Takashima Seiji
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 40 Pages: 14562-14573
  • DOI: 10.1074/jbc.ra119.008544
  • Peer Reviewed
• [Journal Article] A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats. (2019)
  • Author(s): Nakajima Y, Ito S, Asakura M, Min KD, Fu HY, Imazu M, Hitsumoto T, Takahama H, Shindo K, Fukuda H, Yamazaki S, Asanuma H, Kitakaze M.
  • Journal Title: J Molecular and Cellular Cardiology Volume: 129 Pages: 257-265
  • DOI: 10.1016/j.yjmcc.2019.03.009
  • Peer Reviewed
• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail Volume: 6 Issue: 2 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Presentation] 不整脈源性右室心筋症（ARVC）を迅速に再現するヒトモデル細胞の樹立 (2020)
  • Author(s): 中村 聡希, 肥後 修一朗, 志波 幹夫, 小濱 康明, 近藤 匠巳, 亀田 聡士, 田端 智香, 井上 裕之, 山崎 悟, 武田 真季, 高島 成二, 宮川 繁, 澤 芳樹, 彦惣 俊吾, 坂田 泰史
  • Organizer: 日本心筋症研究会
  • Invited
• [Presentation] Cardiac-specific MicroRNAs Increase after Myocardial Reperfusion in the Ischemic Region (2019)
  • Author(s): Satoru Yamazaki, Shuji Shimizu，Masafumi Kitakaze，Toshiaki Shishido，Masaru Sugimachi
  • Organizer: 国際心臓研究会（ISHR）日本部会
  • Int'l Joint Research
• [Presentation] Hypoxia Upregulates Cartilage Intermediate Layer Protein 1 (CILP-1) and Contributes to the Suppression of TGF-β Signaling in Cardiac Fibroblasts (2019)
  • Author(s): Tatsuro Hitsumoto, Satoru Yamazaki, Hiroki Fukuda, Ui Fu, Hiroshi Asanuma, Shin ito, Masafumi Kitakaze
  • Organizer: 国際心臓研究会（ISHR）日本部会
  • Int'l Joint Research
• [Presentation] The c-fos mRNA expression reveals persistent myocardial stretch in the right ventricle during asphyxiated cardiac arrest (2019)
  • Author(s): Sachiko Kadowaki, Satoru Yamazaki, Yasuhiro Kotani, Tatsunori Tsuji, Naoya Sakoda, Yasuyuki Kobayashi, Naohiro Horio, Takuya Goto, Genya Muraoka, Susumu Ozawa, Takanori Suezawa, Yosuke Kuroko, Atsushi Tateishi, Shuji Shimizu, Shingo Kasahara
  • Organizer: ESC Congress
  • Int'l Joint Research