Research on therapy for brain infarction targeting innate immunity

• Project/Area Number: 26461301
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Fukuoka Dental College
• Principal Investigator: Ooboshi Hiroaki 福岡歯科大学, 口腔歯学部, 教授 (10311838)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脳梗塞 / 自然免疫 / マクロファージ / DAMPs / スカベンジャー受容体 / 遺伝子治療 / 周皮細胞

Outline of Final Research Achievements

Immune responses following stroke appears an important factor for tissue damages. Our previous studies have shown that innate immune responses, including infiltrating macrophages and γδT lymphocytes, lead to deterioration of ischemic damages. Furthermore, we found that peroxiredoxin (Prx), an endogenous antioxidant, was identified as a novel damage-associated molecular patterns (DAMPs). Therefore, we examined the mechanisms that reduce damages from the innate immune responses after brain ischemia. We found that DAMPS were cleared by the infiltrating macrophages and transcriptional factors MAFB and class A scavenger receptor MSR1 are key factors of resolution by the macrophages. These findings indicate that targeting the innate immunity may become a novel approach for stroke treatment.

Research Products

• [Journal Article] Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy. (2018)
  • Author(s): Tanaka S, Ninomiya T, Katafuchi R, Masutani K, Tsuchimoto A, Tokumoto M, Hirakata H, Ooboshi H, Kitazono T, Tsuruya K
  • Journal Title: Nephrol Dial Transplant Volume: 印刷中 Issue: 6 Pages: 963-971
  • DOI: 10.1093/ndt/gfx223
  • Peer Reviewed
• [Journal Article] Mafb prevents excess inflammation after ischemic stroke by accelerating clearance of danger signals through MSR1. (2017)
  • Author(s): 1)Shichita T, Ito M, Morita R, Komai K, Noguchi Y, Ooboshi H, Koshida R, Takahashi S, Kodama T, Yoshimura A.
  • Journal Title: Nat Med. Volume: in press Issue: 6 Pages: 723-732
  • DOI: 10.1038/nm.4312
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypercalcemia induced acute kidney injury in an elderly patient with osteoporosis who received alphacalcidol in response to denosumab-induced hypocalcemia. (2017)
  • Author(s): Yamada S, Matsuo M, Tokumoto M, Ooboshi H
  • Journal Title: Nephrology (Carlton) Volume: 22 Issue: 7 Pages: 572-573
  • DOI: 10.1111/nep.12843
  • Peer Reviewed
• [Journal Article] Left Atrial Size and Long‐Term Risk of Recurrent Stroke After Acute Ischemic Stroke in Patients With Nonvalvular Atrial Fibrillation (2017)
  • Author(s): Ogata Toshiyasu、Matsuo Ryu、Kiyuna Fumi、Hata Jun、Ago Tetsuro、Tsuboi Yoshio、Kitazono Takanari、Kamouchi Masahiro、the FSR Investigators
  • Journal Title: Journal of the American Heart Association Volume: 6 Issue: 8
  • DOI: 10.1161/jaha.117.006402
  • Peer Reviewed / Open Access
• [Journal Article] Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke (2017)
  • Author(s): Matsuo Ryu、Yamaguchi Yuko、Matsushita Tomonaga、Hata Jun、Kiyuna Fumi、Fukuda Kenji、Wakisaka Yoshinobu、Kuroda Junya、Ago Tetsuro、Kitazono Takanari、Kamouchi Masahiro、on behalf of the Fukuoka Stroke Registry Investigators†
  • Journal Title: Stroke Volume: 48 Issue: 11 Pages: 3049-3056
  • DOI: 10.1161/strokeaha.117.018132
  • Peer Reviewed / Open Access
• [Journal Article] Impact of blood urea nitrogen to creatinine ratio on mortality and morbidity in hemodialysis patients: The Q-Cohort Study. (2017)
  • Author(s): Tanaka S, Ninomiya T, Taniguchi M, Tokumoto M, Masutani K, Ooboshi H, Kitazono T, Tsuruya K.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 14910-14910
  • DOI: 10.1038/s41598-017-14205-2
  • Peer Reviewed / Open Access
• [Journal Article] Total phosphate elimination is negatively associated with increased serum fibroblast growth factor 23 levels in patients who undergo peritoneal dialysis (2017)
  • Author(s): Yamada S, Tsuruya K, Tokumoto M, Yoshida H, Tatsumoto N, Ooboshi H, Kitazono T
  • Journal Title: Ther Apher Dial Volume: 21 Issue: 1 Pages: 71-78
  • DOI: 10.1111/1744-9987.12478
  • Peer Reviewed
• [Journal Article] DAMPs (damage-associated molecular patterns)と炎症 (2016)
  • Author(s): 大星博明、七田崇
  • Journal Title: 日本臨床 Volume: 74 Pages: 573-578
• [Journal Article] Comparison of oral versus intravenous vitamin D receptor activator in reducing infection-related mortality in hemodialysis patients: the Q-Cohort Study (2016)
  • Author(s): Tanaka S, Ninomiya T, Taniguchi M, Fujisaki K, Tokumoto M, Hirakata H, Ooboshi H, Kitazono T, Tsuruya K
  • Journal Title: Nephrol Dial Transplant Volume: 31 Issue: 7 Pages: 1152-1160
  • DOI: 10.1093/ndt/gfw205
  • Peer Reviewed
• [Journal Article] Factors associated with the serum myostatin level in patients undergoing peritoneal dialysis: potential effects of skeletal muscle mass and vitamin d receptor activator use (2016)
  • Author(s): Yamada S, Tsuruya K, Yoshida H, Tokumoto M, Ueki K, Ooboshi H, Kitazono T
  • Journal Title: Calcif Tissue Int Volume: 99 Issue: 1 Pages: 13-22
  • DOI: 10.1007/s00223-016-0118-6
  • Peer Reviewed
• [Journal Article] Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats. (2016)
  • Author(s): Yamada S, Tokumoto M, Tatsumoto N, Tsuruya K, Kitazono T, Ooboshi H
  • Journal Title: Life Sci Volume: 146 Pages: 117-23
  • Peer Reviewed
• [Journal Article] Pseudohyperchloraemia caused by long-term use of analgesic containing bromovaleryl urea. (2016)
  • Author(s): Yamada S, Tokumoto M, Ooboshi H
  • Journal Title: Nephrology (Carlton) Volume: 21 Issue: 2 Pages: 161-2
  • DOI: 10.1111/nep.12566
  • Peer Reviewed
• [Journal Article] Possible involvement of basic FGF in the upregulation of PDGFRβ in pericytes after ischemic stroke (2016)
  • Author(s): Nakamura K, Arimura K, Nishimura A, Tachibana M, Yoshikawa Y, Makihara N, Wakisaka Y, Kuroda J, Kamouchi M, Ooboshi H, Kitazono T, Ago T
  • Journal Title: Brain Research Volume: 1630 Pages: 98-108
  • DOI: 10.1016/j.brainres.2015.11.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fetuin-A decrease induced by a low-protein diet enhances vascular calcification in uremic rats with hyperphosphatemia. (2015)
  • Author(s): Yamada S, Tokumoto M, Tsuruya K, Tatsumoto N, Noguchi H, Kitazono T, Ooboshi H
  • Journal Title: Am J Physiol Renal Physiol Volume: 309 Issue: 8 Pages: F744-F754
  • DOI: 10.1152/ajprenal.00017.2015
  • Peer Reviewed
• [Journal Article] Day-by-Day Blood Pressure Variability and Functional Outcome After Acute Ischemic Stroke: Fukuoka Stroke Registry (2015)
  • Author(s): Fukuda K, Kai H, Kamouchi M, Hata J, Ago T, Nakane H, Imaizumi T, Kitazono T
  • Journal Title: Stroke Volume: 46 Issue: 7 Pages: 1832-1839
  • DOI: 10.1161/strokeaha.115.009076
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Factors associated with serum soluble inhibitors of Wnt-β-catenin signaling (sclerostin and dickkopf-1) in patients undergoing peritoneal dialysis. (2015)
  • Author(s): Yamada S, Tsuruya K, Tokumoto M, Yoshida H, Ooboshi H, Kitazono T
  • Journal Title: Nephrology (Carlton) Volume: 20 Issue: 4 Pages: 639-45
  • DOI: 10.1111/1744-9987.12292
  • Peer Reviewed
• [Journal Article] Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model. (2015)
  • Author(s): Yamada S, Tatsumoto N, Tokumoto M, Noguchi H, Ooboshi H, Kitazono T, Tsuruya K
  • Journal Title: Calcif Tissue Int Volume: 96 Issue: 4 Pages: 347-358
  • DOI: 10.1007/s00223-014-9929-5
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor 23, but not parathyroid hormone, is associated with urinary phosphate regulation in patients on peritoneal dialysis. (2015)
  • Author(s): Yamada S, Tsuruya K, Tokumoto M, Yoshida H, Hasegawa S, Tanaka S, Eriguchi M, Nakano T, Masutani K, Ooboshi H, Kitazono T
  • Journal Title: Ther Apher Dial Volume: 19 Issue: 1 Pages: 73-80
  • DOI: 10.1111/1744-9987.12221
  • Peer Reviewed
• [Journal Article] A CADASIL-like case with a novel noncysteine mutation of the NOTCH3 gene and granular deposits in the renal arterioles. (2015)
  • Author(s): Nakamura K, Ago T, Tsuchimoto A, Noda N, Nakamura A, Ninomiya T, Uchiumi T, Tsuruya K, Kamouchi M, Ooboshi H, Kitazono T
  • Journal Title: Case Rep Neurol Med Volume: 2015 Pages: 431461-431461
  • DOI: 10.1155/2015/431461
  • Peer Reviewed / Open Access
• [Journal Article] Plasma S100A12 is associated with functional outcome after ischemic stroke: Research for Biomarkers in Ischemic Stroke. (2014)
  • Author(s): Wakisaka Y, Ago T, Kamouchi M, Kuroda J, Matsuo R, Hata J, Gotoh S, Isomura T, Awano H, Suzuki K, Fukuda K, Okada Y, Kiyohara Y, Ooboshi H, Kitazono T; REBIOS Investigators.
  • Journal Title: J Neurol Sci Volume: 340 Issue: 1-2 Pages: 75-9
  • DOI: 10.1016/j.jns.2014.02.031
  • Peer Reviewed
• [Journal Article] Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. (2014)
  • Author(s): Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T
  • Journal Title: Am J Physiol Renal Physiol Volume: 306 Issue: 12 Pages: F1418-F1428
  • DOI: 10.1152/ajprenal.00633.2013
  • Peer Reviewed
• [Journal Article] Impact of the 1425G/A polymorphism of PRKCH on the recurrence of ischemic stroke: Fukuoka Stroke Registry. (2014)
  • Author(s): Matsuo R, Ago T, Hata J, Kuroda J, Wakisaka Y, Sugimori H, Kitazono T, Kamouchi M; FSR Investigators.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 23 Issue: 6 Pages: 1356-1361
  • DOI: 10.1016/j.jstrokecerebrovasdis.2013.11.011
  • Peer Reviewed
• [Presentation] 介護老人保健施設における肺炎患者の嚥下造影検査の解析 (2018)
  • Author(s): 山野貴史, 梅野悠太, 杉野真理子, 鵜木あゆみ, 内藤徹, 中島與志行, 大星博明
  • Organizer: 第41回日本嚥下医学会
• [Presentation] MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1 (2017)
  • Author(s): Shichita T, Ooboshi H, Takahashi S, Kodama T, Yoshimura A
  • Organizer: 第28回国際脳循環代謝学会 Brain 2017
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2017-04-01
  • Int'l Joint Research
• [Presentation] Usefulness of bright arterial appearance in ASL MR perfusion image (2017)
  • Author(s): Kanazawa Y, Arakawa S, Morioka T, Ago T, Kitazono T, Ooboshi H
  • Organizer: 第28回国際脳循環代謝学会 Brain 2017
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2017-04-01
  • Int'l Joint Research
• [Presentation] 経口吸着剤AST-120の腎機能に及ぼす影響：無作為化試験のメタ解析 (2017)
  • Author(s): 田中茂, 二宮利治, 徳本正憲, 大星博明, 鶴屋和彦, 北園孝成
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] 血液透析患者における尿素窒素・クレアチニン比と死亡、合併症罹患の関連：Qコホート研究 (2017)
  • Author(s): 田中茂, 二宮利治, 谷口正智, 徳本正憲, 大星博明, 鶴屋和彦, 北園孝成
  • Organizer: 第62回日本透析医学会学術集会・総会
• [Presentation] IgA腎症患者における血尿と末期腎不全発症リスク (2017)
  • Author(s): 田中茂, 片渕律子, 徳本正憲, 土本晃裕, 大星博明, 鶴屋和彦, 北園孝成
  • Organizer: 第47回日本腎臓学会東部学術大会
• [Presentation] 長期的血圧変動に及ぼす睡眠時無呼吸症候群の影響：職域集団における検討 (2017)
  • Author(s): 寒水康雄, 松村潔, 守永友希, 井上美奈子, 坂田智子, 大石絵美, 後藤健一, 福原正代, 大坪俊夫, 大星博明, 北園孝成
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1 (2017)
  • Author(s): Shichita T, Ooboshi H, Yoshimura A
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] The protective effects of caloric restriction on phosphate-induced calcification via the upregulation of SIRT1 in human vascular smooth muscle cells (2016)
  • Author(s): Tokumoto M, Yamada S, Tsuruya K, Kitazono T, Ooboshi H
  • Organizer: 2016年アメリカ腎臓病学会
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-15
• [Presentation] Neurovascular protectionによる創薬研究 (2016)
  • Author(s): 大星博明
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] A pivotal role of peroxiredoxin in the evolution of brain infarction (2016)
  • Author(s): Hiroaki Ooboshi
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Venice, Italy
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] A pivotal role of peroxiredoxin in the evolution of brain infarction. (2016)
  • Author(s): Ooboshi H, Shichita T, Yoshimura A
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: ベネチア、イタリア
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Comparative effectiveness of oral and injectable vitamin d receptor activator on infectious mortality in hemodialysis patients: the Q Cohort Study. (2015)
  • Author(s): Tanaka S, Ninomiya T, Taniguchi M, Tokumoto M, Hirakata H, Ooboshi H, Tsuruya K, and Kitazono T
  • Organizer: アメリカ腎臓病学会2015
  • Place of Presentation: サンジエゴ、米国
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] The precedence of the reduced osteopontin expression and the increased calcium phosphate nanoparticle to the calcification by phosphate load with normal fasting glucose level in human vascular smooth muscle cells. (2015)
  • Author(s): Tokumoto M, Yamada S, Tsuruya K, Kitazono T, Ooboshi H
  • Organizer: アメリカ腎臓病学会2015
  • Place of Presentation: サンジエゴ、米国
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] 脳梗塞の病態と新規治療開発の将来像－自然免疫を標的とした脳梗塞治療 (2015)
  • Author(s): 大星博明
  • Organizer: 第27回日本脳循環代謝学会
  • Place of Presentation: 富山市国際会議場
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] Neurovascular unitを守る治療研究最前線－主に免疫細胞の立場から (2015)
  • Author(s): 大星博明
  • Organizer: 第56回日本神経学会総会
  • Place of Presentation: 新潟 朱鷺メッセ
  • Year and Date: 2015-05-23
  • Invited
• [Presentation] DAMPsによる脳梗塞後の炎症とその終焉 (2014)
  • Author(s): 七田崇、大星博明、吉村昭彦
  • Organizer: 第26回日本脳循環代謝学会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-22
  • Invited
• [Presentation] Differential effects of dietary phosphate restriction and protein restriction on malnutrition, inflammation and vascular calcification in uremic rats (2014)
  • Author(s): Yamada S, Tokumoto M, Tatsumoto N, Ooboshi H, Tsuruya K, and Kitazono T
  • Organizer: 2014年アメリカ腎臓病学会
  • Place of Presentation: フィラデルフィア、米国
  • Year and Date: 2014-11-15
• [Presentation] The etidronate disodium hydrate directly inhibits both initiation and progression of phosphate-induced calcification in human vascular smooth muscle cells. (2014)
  • Author(s): Tokumoto M, Yamada S, Fujino T, Tsuruya K, Kitazono T, Ooboshi H
  • Organizer: 2014年アメリカ腎臓病学会
  • Place of Presentation: フィラデルフィア、米国
  • Year and Date: 2014-11-14
• [Presentation] Innate immune response as a novel therapeutic target of brain infarction. (2014)
  • Author(s): Hiroaki Ooboshi
  • Organizer: International Symposium on Mechanisms of Innate immune Immunity, Cell Death and Inflammation
  • Place of Presentation: ゲント、ベルギー
  • Year and Date: 2014-09-25
  • Invited
• [Book] 脳卒中病態学のススメ (2018)
  • Author(s): 大星博明
  • Total Pages: 354
  • Publisher: 南山堂
  • ISBN: 9784525248512
• [Book] Acute brain impairment (2017)
  • Author(s): Ooboshi H
  • Total Pages: 348
  • Publisher: Royal Society of Chemistry
  • ISBN: 9781782629504
• [Book] DAMPs (damage-associated molecular patterns)と炎症. 脳卒中 -新時代の治療を求めて- (2016)
  • Author(s): 大星博明、七田崇
  • Publisher: 日本臨床社
• [Book] 無症候性脳出血とmicrobleeds. 脳血管障害治療最前線 (2014)
  • Author(s): 大星博明
  • Total Pages: 421
  • Publisher: 中山書店
• [Book] 虚血による神経障害のメカニズム-脳梗塞と炎症. 最新臨床脳卒中学(上) (2014)
  • Author(s): 七田崇、吉村昭彦、大星博明
  • Total Pages: 735
  • Publisher: 日本臨床社
• [Book] 脳出血慢性期の治療. 最最新臨床脳卒中学(下) (2014)
  • Author(s): 大星博明
  • Total Pages: 711
  • Publisher: 日本臨床社