Elucidation of microRNA-mediated signaling in cerebral vasospasm

• Project/Area Number: 17K10848
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Saitama Medical University
• Principal Investigator: Kikkawa Yuichiro 埼玉医科大学, 医学部, 客員准教授 (80423515)
• Co-Investigator(Kenkyū-buntansha): 栗田 浩樹 埼玉医科大学, 医学部, 教授 (70262003) ; 林 健 埼玉医科大学, 医学部, 教授 (40314679)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脳血管攣縮 / くも膜下出血 / microRNA

Outline of Final Research Achievements

The aim of this study was to explore the role of microRNA(miR) in the development of cerebral vasospasm following subarachnoid hemorrhage (SAH). Peripheral blood and cerebro-spinal fluid (CSF) samples were collected from SAH patients, and microarray analysis and PCR analysis were performed. miR-15a expression was significantly increased in both the CSF and plasma, with a peak around 3 to 5 days after SAH, whereas the expression of Kruppel-like factor 4 (KLF4) was significantly decreased around 1 to 3 days after SAH and remained lower than in controls. Our results suggest that an early and persistent decrease in KLF4 followed by an increase in miR-15a may contribute to the altered vascular phenotype, resulting in development of cerebral vasospasm.

Academic Significance and Societal Importance of the Research Achievements

近年、血管恒常性維持における様々なmicroRNA(miR)の関与が示唆されているが、脳血管攣縮発症におけるその役割や機能に関しては、ほとんど研究されていない。本研究では、血管新生、血管増殖に関与する可能性があるmiR15aの発現と、miR15aを介して抗増殖、抗血管新生作用を有すると考えられるKLF4の有意な発現変化を明らかにし、これにより、miRによる遺伝子発現制御機構がSAH後の脳血管収縮性変化の獲得に関与している可能性が示唆された。分泌型miRNAが血液や髄液中で安定しして存在していることから、今後、臨床上有用な生物マーカーとなる可能性を秘めている。

Research Products

• [Journal Article] Clinical Features of Neurogenic Pulmonary Edema in Patients With Subarachnoid Hemorrhage (2020)
  • Author(s): Tatsuki Kimura, Tomoya Kamide, Koki Onodera, Shinya Tabata, Aoto Shibata, Kaima Suzuki, Ririko Takeda, Toshiki Ikeda, Yuichiro Kikkawa, Satoshi Iihoshi, Shinya Kohyama, Hiroki Kurita
  • Journal Title: World Neurosurg. Volume: 135 Pages: e505-e509
  • DOI: 10.1016/j.wneu.2019.12.060
  • Peer Reviewed
• [Journal Article] Predictors of the Resolution of Cavernous Sinus Syndrome Caused by Large/Giant Cavernous Carotid Aneurysms After Parent Artery Occlusion With High-Flow Bypass (2019)
  • Author(s): Yuichiro Kikkawa, Tomomichi Kayahara, Akio Teranishi, Aoto Shibata, Kaima Suzuki, Tomoya Kamide, Toshiki Ikeda, Hiroki Kurita
  • Journal Title: World Neurosurg. Volume: 132 Pages: e637-e644
  • DOI: 10.1016/j.wneu.2019.08.059
  • Peer Reviewed
• [Journal Article] Ruptured Intrameatal Anterior Inferior Cerebellar Artery Aneurysm Associated With Obstructed Internal Auditory Artery in a Patient With Sudden Hearing Loss and Vertigo (2019)
  • Author(s): Yuichiro Kikkawa, Kaima Suzuki, Akio Teranishi, Taichi Tachikawa, Hiroki Kurita
  • Journal Title: Acta Neurochir (Wien) Volume: 161(2) Issue: 2 Pages: 403-406
  • DOI: 10.1007/s00701-018-3771-x
  • Peer Reviewed
• [Journal Article] Clinical and neuropathologic analysis of interacerebral hemorrhage in patients with cerebral amyloid angiopathy. (2018)
  • Author(s): Yanagawa T, Takao M, Yasuda M, Kamide T, Sato H, Suzuki K, Ikeda T, Kikkawa Y, Kurita H
  • Journal Title: Clin Neurol Neurosurg Volume: 176 Pages: 110-115
  • DOI: 10.1016/j.clineuro.2018.11.020
  • Peer Reviewed
• [Journal Article] 専門医に求められる最新の知識. 脳血管攣縮の病態と治療: 最新の知見 (2018)
  • Author(s): 吉川雄一郎
  • Journal Title: 脳神経外科速報 Volume: 28 (11) Pages: 1100-1107
• [Journal Article] The dose of direct oral anticoagulants and outcomes of intracerebral hemorrhage: Preliminary findings. (2018)
  • Author(s): Suzuki K, Kato Y, Hayashi T, Maruyama H, Kikkawa Y, Kurita H
  • Journal Title: Clin Neurol Neurosurg Volume: 174 Pages: 63-67
  • DOI: 10.1016/j.clineuro.2018.09.011
  • Peer Reviewed
• [Journal Article] Results of Early High-Flow Bypass and Trapping for Ruptured Blood Blister-Like Aneurysms of the Internal Carotid Artery (2017)
  • Author(s): Kikkawa Y, Ikeda T, Takeda R, Nakajima H, Ogura T, Ooigawa H, Kurita H
  • Journal Title: World Neurosurg Volume: 105 Pages: 470-477
  • DOI: 10.1016/j.wneu.2017.06.033
  • Peer Reviewed
• [Journal Article] Multiple simultaneous intracerebral hemorrhages: Clinical presentations and risk factors. (2017)
  • Author(s): Yamaguchi Y, Takeda R, Kikkawa Y, Ikeda T, Suzuki K, Shibata A, Tiezzi G, Araki R, Kurita H
  • Journal Title: J Neurol Sci Volume: 383 Pages: 35-38
  • DOI: 10.1016/j.jns.2017.10.005
  • Peer Reviewed
• [Presentation] 破裂脳動脈瘤患者における持続脳槽洗浄と多剤薬物治療によるスパズム予防の治療成績 (2019)
  • Author(s): 小野寺康輝、吉川雄一郎、田端晋也、松澤良、柴田碧人、吉川信一朗、武田純一、上出智也、池田俊貴、高橋秀寿、神山信也、高尾昌樹、栗田浩樹
  • Organizer: 第35回スパズム・シンポジウム
• [Presentation] くも膜下出血後の髄液・血液中のmiR15aの発現変化とその役割 (2018)
  • Author(s): 吉川雄一郎、木村辰規、松澤良、栢原智道、柴田碧人、武田純一、上出智也、池田俊貴、栗田浩樹
  • Organizer: 第61回日本日本脳循環代謝学会学術集会
• [Presentation] Microcirculatory Impairment is Caused by Independent Mechanisms From Major Arterial Spasm Both in the Acute and Chronic Phase After Experimental SAH (2018)
  • Author(s): Kikkawa Y, Kamide T, Uramaru K, Suzuki K, Takeda R, Tsuchiya R, Ikeda R, Shibata A, Kurita H
  • Organizer: International Stroke Conference 2018
  • Int'l Joint Research
• [Book] Neurovascular Events after Subarachnoid Hemorrhage (2017)
  • Author(s): Kikkawa Y et al.: Sasaki T, Ohkuma H, Kanamaru K, Suzuki M (eds):
  • Total Pages: 156
  • Publisher: NARUNIA Inc