Functional analysis of cholesterol-related long non-coding RNAs and their clinical application

• Project/Area Number: 20K08904
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kyoto University
• Principal Investigator: Horie Takahiro 京都大学, 医学研究科, 助教 (20565577)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 非コードRNA / 心血管代謝性疾患 / コレステロール / ノンコーディングRNA / 動脈硬化

Outline of Research at the Start

ヒト遺伝子の蛋白となる領域はわずか2%程度であり、残りの領域から蛋白にならない多くの非コードRNAが作られている。200塩基長以上の長鎖非コードRNA(lncRNA)についてその重要性が明らかとなりつつある。理研のFANTOM5データ解析からは、ヒトには約28000のlncRNA が発現し、約70％が機能を有することが示唆されている。しかし、個々のlncRNAの働きはほとんどが明らかでない。本研究はこれらの機能を明らかにし、脂質代謝異常や動脈硬化疾患等への治療応用への橋渡しを行う事を目的とする。

Outline of Final Research Achievements

Protein-encoding regions of the human genome account for only about 2%, and many non-coding RNAs (ncRNAs) are transcribed from the remaining regions. Developments in microRNA research, which are one of the short ncRNAs, have revealed that they are involved in various physiological and pathological conditions. On the other hand, the functions of long ncRNAs (lncRNAs), which are ncRNAs with a base length of 200 bases or longer, are largely unknown. In this study, we focused on the cholesterol-related lncRNAs and clarified their functions and roles.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会を迎える日本において心筋梗塞や脳梗塞などの動脈硬化性疾患は重要な疾患であり、新規治療の開発は急務である。動脈硬化性疾患とコレステロール代謝は密接な関係があり、スタチンやPCSK9阻害剤などが開発されその有効性が示されている。本研究ではコレステロール代謝にかかわる新規lncRNAを見出し、その機能を明らかにする。それらを制御することによる新たな治療開発などの臨床応用につなげることを目的とする。本研究は新規治療標的としてのシーズに加え、次世代の研究領域の発展につながる可能性もあり、新規性・独自性に加えて医学・薬学さらには科学の発展への貢献も高いと考える

Research Products

• [Journal Article] MicroRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity. (2021)
  • Author(s): Horie T, Nakao T, Miyasaka Y, Nishino T, Matsumura S, Nakazeki F, Ide Y, Kimura M, Tsuji S, Ruiz Rodriguez R, WatanabeT, Yamasaki T, Xu S, Otani C, Miyagawa S, Matsushita K, Sowa N, Omori A, Tanaka J, Nishimura C, Picciotto MR, Inoue H, Watanabe D, Nakamura K, Sasaki T, Kimura T, Ono K, et al.
  • Journal Title: Nat Commun. Volume: 12 Issue: 1 Pages: 843-843
  • DOI: 10.1038/s41467-021-21107-5
  • NAID: 120006958077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Non-coding RNAs in Vascular Diseases. (2020)
  • Author(s): Ono K, Horie T, Baba O, Kimura M, Tsuji S, Ruiz Rodriguez R, Sawa M, Kimura T.
  • Journal Title: FEBS Lett. Volume: in press Issue: 22 Pages: 6315-6330
  • DOI: 10.1111/febs.15678
  • Peer Reviewed / Open Access
• [Journal Article] LincRNA alleviates cardiac systolic dysfunction under pressure overload. (2020)
  • Author(s): Kuwabara Y, Tsuji S, Nishiga M, Izuhara M, Ito S, Nagao K, Horie T, Watanabe S, Koyama S, Kiryu H, Nakashima Y, Baba O, Nakao T, Nishino T, Sowa N, Miyasaka Y, Hatani T, Ide Y, Nakazeki F, Kimura M, Yoshida Y, Inada T, Kimura T, Ono K.
  • Journal Title: Commun Biol. Volume: 3 Issue: 1 Pages: 434-434
  • DOI: 10.1038/s42003-020-01164-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity. (2020)
  • Author(s): Kimura M, Horie T, Baba O, Ide Y, Tsuji S, Ruiz Rodriguez R, Watanabe T, Yamasaki T, Otani C, Xu S, Miyasaka Y, Nakashima Y, Kimura T, Ono K.
  • Journal Title: EMBO Reports Volume: 21 Issue: 4
  • DOI: 10.15252/embr.201948389
  • NAID: 120006936405
  • Peer Reviewed / Open Access
• [Journal Article] ABLE-MET Investigators. Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial. (2020)
  • Author(s): Ono K, Wada H, Satoh-Asahara N, Inoue H, Uehara K, Funada J, Ogo A, Horie T, Fujita M, Shimatsu A, Hasegawa K.
  • Journal Title: Am J Cardiovasc Drugs. Volume: 20 Issue: 3 Pages: 283-293
  • DOI: 10.1007/s40256-019-00381-1
  • Peer Reviewed
• [Journal Article] Utility of collagen-derived peptides as markers of organ injury in patients with acute heart failure. (2020)
  • Author(s): Nagao K, Tamura A, Sato Y, Hata R, Kawase Y, Kadota K, Horie T, Sowa N, Nishiga M, Ono K, Inada T, Tanaka M.
  • Journal Title: Open Heart Volume: 7 Issue: 1 Pages: e001041-e001041
  • DOI: 10.1136/openhrt-2019-001041
  • Peer Reviewed
• [Presentation] High-intensity statins work regardless of age. (Debate: Lipid Management: Is there Anything Beyond LDL?) (2020)
  • Author(s): Takahiro Horie
  • Organizer: 第84回 日本循環器学会
  • Invited
• [Presentation] miR-33b has more impact on the formation of insulin resistance and atherosclerosis than miR-33a. (2020)
  • Author(s): Takahiro Horie, Satoshi Koyama, Takeshi Kimura, Koh Ono
  • Organizer: 第84回 日本循環器学会
• [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/