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 / 人工核酸 / iPSC

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] MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons (2019)
  • Author(s): Nakazeki F、Tsuge I、Horie T、Imamura K、Tsukita K、Hotta A、Baba O、Kuwabara Y、Nishino T、Nakao T、Nishiga M、Nishi H、Nakashima Y、Ide Y、Koyama S、Kimura M、Tsuji S、Naitoh M、Suzuki S、Izumi Y、Kawarai T、Kaji R、Kimura T、Inoue H、Ono K
  • Journal Title: Clinical Science Volume: 133 Issue: 4 Pages: 583-595
  • DOI: 10.1042/cs20180980
  • NAID: 120006937614
  • Peer Reviewed / Open Access
• [Journal Article] Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction (2018)
  • Author(s): Hakuno Daihiko、Kimura Masahiro、Ito Shinji、Satoh Junko、Nakashima Yasuhiro、Horie Takahiro、Kuwabara Yasuhide、Nishiga Masataka、Ide Yuya、Baba Osamu、Nishi Hitoo、Nakao Tetsushi、Nishino Tomohiro、Nakazeki Fumiko、Koyama Satoshi、Hanada Ritsuko、Randolph Ruiz R.、Endo Jin、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-17
  • DOI: 10.1038/s41598-018-35194-w
  • NAID: 120006645320
  • Peer Reviewed / Open Access
• [Journal Article] SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo (2018)
  • Author(s): Nishino T、Horie T、Baba O、Sowa N、Hanada R、Kuwabara Y、Nakao T、Nishiga M、Nishi H、Nakashima Y、Nakazeki F、Ide Y、Koyama S、Kimura M、Nagata M、Yoshida K、Takagi Y、Nakamura T、Hasegawa K、Miyamoto S、Kimura T、Ono K.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 38 Issue: 10 Pages: 2460-2473
  • DOI: 10.1161/atvbaha.118.311409
  • Peer Reviewed / Open Access
• [Journal Article] Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: relationships with myocardial collagen expression (2018)
  • Author(s): Nagao Kazuya、Inada Tsukasa、Tamura Akinori、Kajitani Kenji、Shimamura Kiyotaka、Yukawa Hiroshi、Aida Kenji、Sowa Naoya、Nishiga Masataka、Horie Takahiro、Makita Toshinori、Ono Koh、Tanaka Masaru
  • Journal Title: ESC Heart Failure Volume: 5 Issue: 6 Pages: 1044-1051
  • DOI: 10.1002/ehf2.12360
  • Peer Reviewed / Open Access
• [Journal Article] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Nakazeki Fumiko、Nishiga Masataka、Horie Takahiro、Nishi Hitoo、Nakashima Yasuhiro、Baba Osamu、Kuwabara Yasuhide、Nishino Tomohiro、Nakao Tetsushi、Ide Yuya、Koyama Satoshi、Kimura Masahiro、Tsuji Shuhei、Sowa Naoya、Yoshida Shigeo、Conway Simon J.、Yanagita Motoko、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8553-8553
  • DOI: 10.1038/s41598-018-27009-9
  • NAID: 120006510274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nakao T, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K.
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 14 Pages: 1-17
  • DOI: 10.1128/mcb.00604-17
  • 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: Circulation Journal Volume: 82 Issue: 5 Pages: 1231-1236
  • DOI: 10.1253/circj.CJ-18-0169
  • NAID: 130006725985
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [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 Issue: 11 Pages: 1304-1314
  • DOI: 10.1016/j.amjcard.2018.02.010
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic impacto 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 Cardiovascular Interv Volume: 11 Issue: 2 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. (2017)
  • 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 Issue: 4 Pages: 1209-1215
  • DOI: 10.1016/j.jvs.2017.08.097
  • 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 Issue: 4 Pages: 433-437
  • DOI: 10.1016/j.carrev.2017.10.007
  • Peer Reviewed
• [Journal Article] on behalf of the CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators. Single-session Versus Staged Procedures for Elective Multi-vessel Percutaneous Coronary Intervention. (2017)
  • 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. Volume: Nov 16. Issue: 11 Pages: 936-944
  • DOI: 10.1136/heartjnl-2017-312117
  • Peer Reviewed / Open Access
• [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): Issue: 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: Arterioscler Thromb Vasc Biol. Volume: 37 Issue: 11 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: Int J Hematol. Volume: 106 Issue: 6 Pages: 811-819
  • DOI: 10.1007/s12185-017-2314-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Smoking cessation reduces the lectin-like low-density lipoprotein receptor index, an independent cardiovascular risk marker of vascular inflammation (2017)
  • 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 and Vessels Volume: 33 Issue: 1 Pages: 9-16
  • DOI: 10.1007/s00380-017-1026-z
  • Peer Reviewed / Open Access
• [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: International Journal of Cardiology Volume: 243 Pages: 1-8
  • DOI: 10.1016/j.ijcard.2017.04.047
  • NAID: 130007900462
  • 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 Issue: 12 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: Circulation Journal Volume: 81 Issue: 12 Pages: 1936-1944
  • DOI: 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: Circulation Journal Volume: 81 Issue: 12 Pages: 1783-1791
  • DOI: 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 Failure Volume: 4 Issue: 2 Pages: 112-121
  • DOI: 10.1002/ehf2.12123
  • 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 Issue: 4 Pages: e0175649-e0175649
  • DOI: 10.1371/journal.pone.0175649
  • NAID: 120006534994
  • 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: American Journal of Cardiology Volume: 印刷中 Issue: 11 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) Issue: 3 Pages: e0172798-e0172798
  • DOI: 10.1371/journal.pone.0172798
  • Peer Reviewed / Open Access
• [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 Issue: 1
  • 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 Cholesterol. (2016)
  • 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: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 1.SREBF1/MicroRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo. (2018)
  • Author(s): Koh Ono
  • Organizer: XVIIIth International Symposium on Atherosclerosis.
  • Int'l Joint Research / Invited
• [Presentation] SREBF1/MicroRNA-33b axis は不安定プラークの形成に重要である (2018)
  • Author(s): 尾野 亘
  • Organizer: 第50回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] Functions of microRNA-33a/b on inflammation and atherosclerosis (2018)
  • Author(s): Koh Ono
  • Organizer: China-Japan International Conference on Atherosclerosis 2018.
  • Int'l Joint Research / Invited
• [Presentation] マイクロRNAと心血管疾患、代謝性疾患 (2018)
  • Author(s): 尾野 亘
  • Organizer: 第66回日本心臓病学会
  • Invited
• [Presentation] MicroRNA-33の欠損は複数の抗炎症経路を介して大動脈瘤の形成を抑制する (2018)
  • Author(s): 尾野 亘
  • Organizer: 第59回日本脈管学会総会
  • Invited
• [Presentation] A Novel Long Intergenic Noncoding RNA, Lionheart, Protects the Heart from Pressure Overload (2018)
  • Author(s): 尾野 亘
  • Organizer: 第83回 日本循環器学会学術集会
  • Invited
• [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] 京都大学循環器内科 分子循環器グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [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)] 遺伝性痙性対麻痺(Hereditary Spastic Paraplegia; HSP)SPG4 に対するmicroRNA-33a抑制療法 (2018)
  • Inventor(s): 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Holder: 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-119251
  • Filing Date: 2018
• [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