Stress response evaluation and novel therapy development in advanced cardiac and pulmonary diseases in children

• Project/Area Number: 16K10067
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Okayama University
• Principal Investigator: TSUKAHARA Hirokazu 岡山大学, 医歯薬学総合研究科, 教授 (90207340)
• Co-Investigator(Kenkyū-buntansha): 馬場 健児 岡山大学, 大学病院, 准教授 (40721767) ; 大月 審一 岡山大学, 大学病院, 教授 (90294454)
• Research Collaborator: MIYAHARA Hiroyuki ; WASHIO Yosuke ; Yoshimoto Junko ; Yashiro Masato
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルギニン代謝 / 一酸化窒素 / 川崎病 / 血管内皮機能 / 酸化ストレス / シトリン欠損症 / 生体マーカー / レドックス制御 / 活性酸素 / 血管内皮 / 心臓疾患 / 血管疾患 / 小児科学 / 小児循環器学

Outline of Final Research Achievements

We performed clinical and translation studies related to advanced cardiac and pulmonary pathologies on the high-class clinical and experimental research backgrounds in Okayama University Hospital. Especially, we took special attention to vascular endothelial function/dysfunction, oxidative/nitrosative stress (redox regulation/dysregulation), nitric oxide production and arginine metabolism in the present work. Thus, we sought to develop adequate management strategies and novel therapeutic approaches for advanced cardiac and pulmonary diseases in children.

Academic Significance and Societal Importance of the Research Achievements

本研究成果に基づいてさらに知見を深めることによって、小児心臓・肺領域の急速進行性病態では進行抑制、完全治癒、慢性遷延性病態では寛解導入、合併症抑止が導かれ、ひいては、患児の日常生活、学校生活、将来生活を含めたQuality of Life（QOL）を向上させる方略が開発されることが期待された。さらに、小児医療の質の向上と医療費の節減に貢献することも期待された。

Research Products

• [Journal Article] Population-based longitudinal study showed that children born small for gestational age faced a higher risk of hospitalisation during early childhood (2019)
  • Author(s): Yoshimoto J, Yorifuji T, Washio Y, Okamura T, Watanabe H, Doi H, Tsukahara H
  • Journal Title: Acta Paediatr Volume: 108 Issue: 3 Pages: 473-478
  • DOI: 10.1111/apa.14507
  • Peer Reviewed
• [Journal Article] Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice (2019)
  • Author(s): Hatayama K, Nosaka N, Yamada M, Yashiro M, Fujii Y, Tsukahara H, Liu K, Nishibori M, Matsukawa A, Morishima T
  • Journal Title: J Med Virol Volume: 91 Issue: 3 Pages: 361-369
  • DOI: 10.1002/jmv.25330
  • Peer Reviewed
• [Journal Article] Early childhood exposure to maternal smoking and Kawasaki Disease: A longitudinal survey in Japan (2019)
  • Author(s): Yorifuji T, Tsukahara H, Doi H
  • Journal Title: Sci Total Environ Volume: 655 Pages: 141-146
  • DOI: 10.1016/j.scitotenv.2018.11.194
  • NAID: 120006900811
  • Peer Reviewed
• [Journal Article] Analysis of factors associated with development of Bacille Calmette-Guerin inoculation site change in patients with Kawasaki disease (2018)
  • Author(s): Araki T, Kodera A, Kitada K, Fujiwara M, Muraoka M, Abe Y, Ikeda M, Tsukahara H
  • Journal Title: J Int Med Res Volume: 46 Issue: 4 Pages: 1640-1648
  • DOI: 10.1177/0300060518760462
  • Peer Reviewed / Open Access
• [Journal Article] Birth order and paediatric allergic disease: A nationwide longitudinal survey (2018)
  • Author(s): Kikkawa T, Yorifuji T, Fujii Y, Yashiro M, Okada A, Ikeda M, Doi H, Tsukahara H
  • Journal Title: Clin Exp Allergy Volume: 48 Pages: 577-585
  • Peer Reviewed
• [Journal Article] Cholesterol metabolism is enhanced in the liver and brain of children with citrin deficiency. (2018)
  • Author(s): Satoshi Hirayama, Hironori Nagasaka, Akira Honda, Haruki Komatsu, Takahiro Kodama, Ayano Inui, Ichiro Morioka, Shunsaku Kaji, Tsuyoshi Ueno, Kenji Ihara, Mariko Yagi, Zenro Kizaki, Kazuhiko Bessho, Hiroki Kondou, Tohru Yorifuji, Hirokazu Tsukahara, Kazumoto Iijima, Takashi Miida
  • Journal Title: J Clin Endocrinol Metab Volume: 103 Issue: 7 Pages: 2488-2497
  • DOI: 10.1210/jc.2017-02664
  • Peer Reviewed / Open Access
• [Journal Article] Anti-High Mobility Group Box-1 Monoclonal Antibody Treatment of Brain Edema Induced by Influenza Infection and Lipopolysaccharide (2018)
  • Author(s): Nosaka N, Hatayama K, Yamada M, Fujii Y, Yashiro M, Wake H, Tsukahara H, Nishibori M, Morishima T
  • Journal Title: J Med Virol Volume: 90 Issue: 7 Pages: 1192-1198
  • DOI: 10.1002/jmv.25076
  • Peer Reviewed
• [Journal Article] Blood asymmetric dimethylarginine and nitrite/nitrate concentrations in short-stature children born small for gestational age with and without growth hormone therapy. (2018)
  • Author(s): Nagasaka H, Morioka I, Takuwa M, Nakacho M, Yoshida M, Ishida A, Hirayama S, Miida T, Tsukahara H, Yorifuji T, Iijima K.
  • Journal Title: J Int Med Res. Volume: ４６ Issue: 2 Pages: 761-772
  • DOI: 10.1177/0300060517723183
  • NAID: 120006425669
  • Peer Reviewed / Open Access
• [Journal Article] Intrauterine and Early Postnatal Exposure to Particulate Air Pollution and Kawasaki Disease: A Nationwide Longitudinal Survey in Japan. (2018)
  • Author(s): Yorifuji T, Tsukahara H, Kashima S, Doi H.
  • Journal Title: J Pediatr. Volume: １９３ Pages: 147-154
  • DOI: 10.1016/j.jpeds.2017.10.012
  • Peer Reviewed
• [Journal Article] Serum Amino Acid Profiling in Citrin-Deficient Children Exhibiting Normal Liver Function During the Apparently Healthy Period. (2018)
  • Author(s): Miyazaki T, Nagasaka H, Komatsu H, Inui A, Morioka I, Tsukahara H, Kaji S, Hirayama S, Miida T, Kondou H, Ihara K, Yagi M, Kizaki Z, Bessho K, Kodama T, Iijima K, Yorifuji T, Matsuzaki Y, Honda A.
  • Journal Title: JIM Rep. Volume: － Pages: 53-61
  • DOI: 10.1007/8904_2018_99
  • ISBN: 9783662586136, 9783662586143
  • Peer Reviewed / Open Access
• [Journal Article] Intracranial Pressure Monitoring for Pediatric Acute Encephalopathy (2017)
  • Author(s): Nosaka N, Tsukahara K, Knaup E, Yabuuchi T, Kikkawa T, Fujii Y, Yashiro M, Yasuhara T, Okada A, Ugawa T, Nakao A, Tsukahara H, Date I.
  • Journal Title: Acta Medica Okayama Volume: 71 Issue: 2 Pages: 179-180
  • DOI: 10.18926/AMO/54987
  • NAID: 120006027005
  • URL: https://ousar.lib.okayama-u.ac.jp/54987
  • Peer Reviewed / Open Access
• [Journal Article] New age-based weight estimation formulae for Japanese children. (2017)
  • Author(s): Nosaka N, Yorifuji T, Knaup E, Tsukahara K, Muguruma T, Okada A, Tsukahara H, Doi H.
  • Journal Title: Pediatr Int. Volume: ５９ Issue: 6 Pages: 727-732
  • DOI: 10.1111/ped.13259
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metabolic pathway catalyzed by Vanin-1 pantetheinase plays a suppressive role in influenza virus replication in human alveolar epithelial A549 cells. (2017)
  • Author(s): Yamashita N, Yashiro M, Ogawa H, Namba H, Nosaka N, Fujii Y, Morishima T, Tsukahara H, Yamada M.
  • Journal Title: Biochem Biophys Res Commun. Volume: ４８９ Issue: 4 Pages: 466-471
  • DOI: 10.1016/j.bbrc.2017.05.172
  • Peer Reviewed
• [Journal Article] Growth hormone activates hepatic and cerebral cholesterol metabolism in small-for-gestational age children without catch-up growth. (2017)
  • Author(s): Hirayama S, Nagasaka H, Nakagawa S, Takuwa M, Nakacho M, Yorifuji T, Kondou H, Tsukahara H, Morioka I, Ishida A, Yamato S, Miida T.
  • Journal Title: J Clin Lipidol. Volume: １１ Issue: 4 Pages: 1032-1042
  • DOI: 10.1016/j.jacl.2017.05.010
  • Peer Reviewed / Open Access
• [Journal Article] Local and Systemic Immune Responses to Influenza A Virus Infection in Pneumonia and Encephalitis Mouse Models. (2017)
  • Author(s): Nagaoka Y, Nosaka N, Yamada M, Yashiro M, Washio Y, Baba K, Morishima T, Tsukahara H.
  • Journal Title: Dis Markers. Volume: ２０１７ Pages: 2594231-2594231
  • DOI: 10.1155/2017/2594231
  • Peer Reviewed / Open Access
• [Journal Article] Gene expression analysis of hypersensitivity to mosquito bite, chronic active EBV infection and NK/T-lymphoma/leukemia (2017)
  • Author(s): Kana Washio, Takashi Oka, Lamia Abdalkader, Michiko Muraoka, Akira Shimada, Megumi Oda, Hiaki Sato, Katsuyoshi Takata, Yoshitoyo Kagami, Norio Shimizu, Seiichi Kato, Hiroshi Kimura, Kazunori Nishizaki, Tadashi Yoshino & Hirokazu Tsukahara
  • Journal Title: Leukemia & Lymphoma Volume: 58 Issue: 11 Pages: 1-12
  • DOI: 10.1080/10428194.2017.1304762
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Five Cases of Pediatric-Onset Bechet’s disease complicated with Myelodysplastic Syndrome (2017)
  • Author(s): Kanamitsu K, Shimada A, Nishiuchi R, Shigemura T, Nakazawa Y, Koike K, Kodama Y, Shinkoda Y, Kawano Y, Yasui K, Sasaki K, Kajiwara R, Tsukahara H, Manabe A.
  • Journal Title: International Journal of Hematology Volume: 105 Issue: 3 Pages: 377-382
  • DOI: 10.1007/s12185-016-2127-7
  • Peer Reviewed
• [Journal Article] Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment (2017)
  • Author(s): Nagasaka H, Komatsu H, et al.
  • Journal Title: Mol Genet Metab Volume: 120 Pages: 207-212
  • Peer Reviewed
• [Journal Article] 酸化ストレス制御と小児疾患治療 (2017)
  • Author(s): 塚原宏一
  • Journal Title: 日児誌 Volume: 121 Pages: 527-535
• [Journal Article] Breastfeeding and Risk of Kawasaki Disease: A Nationwide Longitudinal Survey in Japan (2016)
  • Author(s): Yorifuji T, Tsukahara H, Doi H.
  • Journal Title: Pediatrics Volume: 137 Issue: 6
  • DOI: 10.1542/peds.2015-3919
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mutating heme oxygenase-1 into a peroxidase causes a defect in bilirubin synthesis associated with microcytic anemia and severe hyperinflammation (2016)
  • Author(s): Greil J, Verga-Falzacappa MV, et al.
  • Journal Title: Haematologica Volume: 101
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 消化管アレルギー - 消化管アレルギーと酸化ストレス (2016)
  • Author(s): 野坂宜之, 籔内俊彦, 塚原宏一
  • Journal Title: 小児内科 Volume: 48 Pages: 1347-1351
• [Journal Article] フリーラジカル 腎疾患との新たな関わり: 酸化ストレスマーカー (2016)
  • Author(s): 塚原宏一, 宮井貴之, 岡田あゆみ
  • Journal Title: 腎と透析 Volume: 81 Pages: 945-951
• [Presentation] 酸化ストレス制御と小児疾患治療 (2016)
  • Author(s): 塚原宏一
  • Organizer: 第119回 日本小児科学会学術集会
  • Place of Presentation: 札幌
• [Book] Human Pathobiochemistry: From Clinical Studies to Molecular Mechanisms (2019)
  • Author(s): Oohashi, T., Tsukahara, H., Ramirez, F., Barber, C.L., Otsuka, F (Editors)
  • Total Pages: 349
  • Publisher: Springer