Elucidation of global metabolic control mechanisms by microRNA-33a/b and development of specific regulatory strategy using artificial nucleic acid

• Project/Area Number: 17H04177
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: Ono Koh 京都大学, 医学研究科, 准教授 (00359275)
• Co-Investigator(Kenkyū-buntansha): 堀江 貴裕 京都大学, 医学研究科, 助教 (20565577)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: マイクロRNA / iPS細胞 / 核酸医薬 / 代謝 / iPSC / 人工核酸

Outline of Final Research Achievements

We revealed that microRNA(miR)-33a/b have essential roles in low HDL-C, atherosclerosis, aortic aneurysm, fibrosis, non-alcoholic steatohepatitis, hypertension, Alzheimer disease, and activation of sympathetic nerve by the use of genetically modified induced pluripotent stem cell and mice. In these experiments, it was shown that miR-33a/b have different target genes in each cell or tissue. Moreover, we developed anti-miR-33a/b oligonucleotides that can selectively suppress the levels of miR-33a or -33b. We applied these oligonucleotides to several disease models and filed a patent for the treatment of aortic aneurysm. We are going to conduct clinical research to identify the clinical application of these oligonucleotides.

Academic Significance and Societal Importance of the Research Achievements

本研究により、microRNA-33a/bが低HDL-C、動脈硬化症、動脈瘤、線維化、NASHを含む慢性炎症、高血圧症、アルツハイマー症、交感神経系の活性化に共通する発症基盤であることが明らかになった。これは我々の作成した遺伝子改変マウスによってのみ明らかにすることができた点であり、学術的意義が高いと考えられる。さらに、miR-33aおよび33bを個別に制御できる架橋型人工核酸を開発し、複数の疾患モデルにおいて治療効果の検討を行っている。すでに大動脈瘤については治療法の特許申請中であり、今後さらに治療可能な疾患が増えることが予想されるため、臨床的・社会的意義も高いと考えられる。

Research Products

• [Journal Article] Impact of Baseline Thrombocytopenia on Bleeding and Mortality after Percutaneous Coronary Intervention (2018)
  • Author(s): Ito Shinya、Watanabe Hirotoshi、Morimoto Takeshi、Yoshikawa Yusuke、Shiomi Hiroki、Shizuta Satoshi、Ono Koh、Yamaji Kyohei、Soga Yoshimitsu、Hyodo Makoto、Shirai Shinichi、Ando Kenji、Horiuchi Hisanori、Kimura Takeshi
  • Journal Title: Am J Cardiol. Volume: 印刷中
  • DOI: 10.1016/j.amjcard.2018.02.010
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circ J Volume: 印刷中 Issue: 5 Pages: 1231-1236
  • DOI: 10.1253/circj.cj-18-0169 10.1253/circj.CJ-18-0169
  • NAID: 130006725985
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Impact of Left Ventricular Ejection Fraction in Patients With Severe Aortic Stenosis. (2018)
  • Author(s): Taniguchi T, Morimoto T, Shiomi H, Ando K, Kanamori N, Murata K, Kitai T, Kadota K, Izumi C, Nakatsuma K, Sasa T, Watanabe H, Kuwabara Y, Makiyama T, Ono K, Shizuta S, Kato T, Saito N, Minatoya K, Kimura T.
  • Journal Title: JACC Cardiovasc Interv. Volume: 11 Pages: 145-157
  • DOI: 10.1016/j.jcin.2017.08.036
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic angiogenesis by local sustained release of microRNA-126 using poly lactic-co-glycolic acid nanoparticles in murine hindlimb ischemia (2018)
  • Author(s): Tsumaru S, Masumoto H, Minakata K, Izuhara M, Yamazaki K, Ikeda T, Ono K, Sakata R, Minatoya K.
  • Journal Title: J Vasc Surg Volume: 印刷中 Pages: 1209-1215
  • DOI: 10.1016/j.jvs.2017.08.097
  • Peer Reviewed / Open Access
• [Journal Article] Single-session versus staged procedures for elective multivessel percutaneous coronary intervention. (2018)
  • Author(s): Toyota T, Morimoto T, Shiomi H, Yamaji K, Ando K, Ono K, Shizuta S, Saito N, Kato T, Kaji S, Furukawa Y, Nakagawa Y, Kadota K, Horie M, Kimura T,
  • Journal Title: Heart (British Cardiac Society) Volume: Nov 16.
  • DOI: 10.1136/heartjnl-2017-312117
  • Peer Reviewed / Open Access
• [Journal Article] Smoking cessation reduces the lectin-like low-density lipoprotein receptor index, an independent cardiovascular risk marker of vascular inflammation. (2018)
  • Author(s): Komiyama Maki、Wada Hiromichi、Ono Koh、Yamakage Hajime、Satoh-Asahara Noriko、Shimada Sayaka、Akao Masaharu、Morimoto Tatsuya、Shimatsu Akira、Takahashi Yuko、Sawamura Tatsuya、Hasegawa Koji
  • Journal Title: Heart Vessels. Volume: 33 Pages: 9-16
  • DOI: 10.1007/s00380-017-1026-z
  • Peer Reviewed / Open Access
• [Journal Article] Preclinical evaluation of a paclitaxel-incorporated nanoparticle-coated balloon in rabbit and porcine models. (2017)
  • Author(s): Yamamoto E, Watanabe S, Bao B, Watanabe H, Nakatsuma K, Izuhara M, Ono K, Nakazawa G, Kimura T, Saito N.
  • Journal Title: Cardiovasc Revasc Med. Volume: 印刷中
  • DOI: 10.1016/j.carrev.2017.10.007
  • Peer Reviewed
• [Journal Article] Impact of Transient or Persistent Contrast-induced Nephropathy on Long-term Mortality After Elective Percutaneous Coronary Intervention. (2017)
  • Author(s): Abe M, Morimoto T, Nakagawa Y, Furukawa Y, Ono K, Kato T, Kadota K, Ando K, Ishii M, Masunaga N, Akao M, Kimura T.
  • Journal Title: Am J Cardiol. Volume: Dec 15;120(12): Pages: 2146-2153
  • DOI: 10.1016/j.amjcard.2017.08.036
  • Peer Reviewed / Open Access
• [Journal Article] Very long-term clinical outcomes after radiofrequency catheter ablation for atrial fibrillation: A large single-center experience. (2017)
  • Author(s): Kawaji T, Shizuta S, Morimoto T, Aizawa T, Yamagami S, Yoshizawa T, Ota C, Onishi N, Sasaki Y, Yahata M, Nakai K, Hayano M, Nakao T, Hanazawa K, Goto K, Doi T, Ono K, Kimura T.
  • Journal Title: Int J Cardiol. Volume: 249 Pages: 204-213
  • DOI: 10.1016/j.ijcard.2017.09.023
• [Journal Article] Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways (2017)
  • Author(s): Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, Ono K.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 37 Pages: 2161-2170
  • DOI: 10.1161/atvbaha.117.309768
  • Peer Reviewed / Open Access
• [Journal Article] Imbalanced expression of polycistronic miRNA in acute myeloid leukemia (2017)
  • Author(s): Kotaki R, Higuchi H, Ogiya D, Katahira Y, Kurosaki N, Yukihira N, Ogata J, Yamamoto H, Mohamad Alba S, Azhim A, Kitajima T, Inoue S, Morishita K, Ono K, Koyama-Nasu R, Kotani A.
  • Journal Title: International Journal of Hematology Volume: 106 Pages: 811-819
  • DOI: 10.1007/s12185-017-2314-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome. (2017)
  • Author(s): Chen Po-Min、Ohno Mikiko、Hiwasa Takaki、Nishi Kiyoto、Saijo Sayaka、Sakamoto Jiro、Morita Yusuke、Matsuda Shintaro、Watanabe Shin、Kuwabara Yasuhide、Ono Koh、Imai Masao、Inoue Katsumi、Murai Tatsuya、Inada Tsukasa、Tanaka Masaru、Kita Toru、Kimura Takeshi、Nishi Eiichiro
  • Journal Title: Int J Cardiol. Volume: 243 Pages: 1-8
  • DOI: 10.1016/j.ijcard.2017.04.047
  • Peer Reviewed
• [Journal Article] Transradial versus transfemoral approach in patients undergoing primary percutaneous coronary intervention for ST-elevation acute myocardial infarction: insight from the CREDO-Kyoto AMI registry. (2017)
  • Author(s): Yamashita Y, Shiomi H, Morimoto T, Yaku H, Kaji S, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Abe M, Akao M, Nagao K, Shizuta S, Ono K, Kimura T
  • Journal Title: Heart Vessels. Volume: 32 Pages: 1936-1944
  • DOI: 10.1007/s00380-017-1021-4
  • Peer Reviewed
• [Journal Article] Asymptomatic Lower Extremity Deep Vein Thrombosis ― Clinical Characteristics, Management Strategies, and Long-Term Outcomes ― (2017)
  • Author(s): Yamashita Y, Shiomi H, Morimoto T, Yoneda T, Yamada C, Makiyama T, Kato T, Saito N, Shizuta S, Ono K, Kimura T.
  • Journal Title: Circ J Volume: 81 Issue: 12 Pages: 1936-1944
  • DOI: 10.1253/circj.cj-17-0445 10.1253/circj.CJ-17-0445
  • NAID: 130006219233
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy (2017)
  • Author(s): Hayano M, Makiyama T
  • Journal Title: Circ J Volume: 81 Issue: 12 Pages: 1783-1791
  • DOI: 10.1253/circj.cj-17-0064 10.1253/circj.CJ-17-0064
  • NAID: 130006219109
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation (2017)
  • Author(s): Satoshi Koyama, Takashi Kuragaichi, Yukihito Sato, Yasuhide Kuwabara, Shunsuke Usami, Takahiro Horie, Osamu Baba, Daihiko Hakuno, Yasuhiro Nakashima, Tomohiro Nishino, Masataka Nishiga, Tetsushi Nakao, Hidenori Arai, Takeshi Kimura, Koh Ono
  • Journal Title: ESC Heart Fail. Volume: 4 Pages: 112-121
  • DOI: 10.1002/ehf2.12123
  • NAID: 120006318903
  • Peer Reviewed / Open Access
• [Journal Article] Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. (2017)
  • Author(s): Morimoto T, Mineharu Y, Ono K, Nakatochi M, Ichihara S, Kabata R, Takagi Y, Cao Y, Zhao L, Kobayashi H, Harada K. H, Takenaka K, Funaki T, Yokota M, Matsubara T, Yamamoto K, Izawa H, Kimura T, Miyamoto S, Koizumi A
  • Journal Title: PLOS ONE Volume: 12
  • DOI: 10.1371/journal.pone.0175649
  • NAID: 120006309308
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Incidence and Prognostic Impact of Heart Failure Hospitalization During Follow-Up After Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (2017)
  • Author(s): Taniguchi T, Horie M, et al.
  • Journal Title: Am J Cardiol. Volume: 印刷中 Pages: 1729-1739
  • DOI: 10.1016/j.amjcard.2017.03.013
  • Peer Reviewed
• [Journal Article] Prevention of Neointimal Formation Using miRNA-126-Containing Nanoparticle-Conjugated Stents in a Rabbit Model. (2017)
  • Author(s): Izuhara M, Kuwabara Y, Saito N, Yamamoto E, Hakuno D, Nakashima Y, Horie T, Baba O, Nishiga M, Nakao T, Nishino T, Nakazeki F, Ide Y, Kimura M, Kimura T, Ono K.
  • Journal Title: PLoS One. Volume: 12(3)
  • DOI: 10.1371/journal.pone.0172798
  • NAID: 120005997927
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cardiac and Noncardiac Causes of Long-Term Mortality in ST-Segment-Elevation Acute Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention. (2017)
  • Author(s): Yamashita Y, Shiomi H, Morimoto T, Yaku H, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Abe M, Nagao K, Shizuta S, Ono K, Kimura T; CREDO-Kyoto AMI Registry Investigators.
  • Journal Title: Circ Cardiovasc Qual Outcomes. Volume: 10
  • DOI: 10.1161/circoutcomes.116.002790
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft CholesterolNovelty and Significance (2017)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res Volume: - Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Novel Long Intergenic Noncoding RNA, Lionheart, Guards the Heart from Pressure Overload (2018)
  • Author(s): Kuwabara Y, Horie T, Baba O, Nishiga M, Nakao M, Nishino T, Nakazeki F, Koyama S, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice (2018)
  • Author(s): Nishino T, Horie T, Baba O, Kuwabara Y, Hakuno D, Nakashima Y, Nakao T, Nishiga M, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] Roles of microRNAs in cardiovascular diseases (2017)
  • Author(s): Koh Ono
  • Organizer: 2nd International Symposium for Noncoding RNA Neo-taxonomy In conjunction with Tokyo RNA Club 23rd meeting
  • Int'l Joint Research / Invited
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Koh Ono
  • Organizer: 43rd Naito Conference Noncoding RNA
  • Int'l Joint Research
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T, Ono K
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Remarks] 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Patent(Industrial Property Rights)] miR-33bノックインマウスによる非アルコール性脂肪肝炎モデル (2018)
  • Inventor(s): 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas