Elucidation of the irreversible mechanism of severe heart failure using biological monitoring murine heart failure model

• Project/Area Number: 15K09139
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: ASANO Yoshihiro 大阪大学, 大学院医学系研究科, 講師 (60527670)
• Co-Investigator(Kenkyū-buntansha): 塚本 蔵 大阪大学, 医学系研究科, 助教 (80589151) ; 加藤 久和 大阪大学, 医学系研究科, 助教 (30589312)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: エピゲノム / 細胞核クロマチン / 難治性心不全 / 分子循環器病学 / 臨床循環器

Outline of Final Research Achievements

Molecular biology and pathological analysis were performed to elucidate the molecular mechanism of refractory severe heart failure. We established our own epigenetic index analysis method for discrimination between irreversible and reversible cardiac muscle and investigated the molecular search and pathology of refractory heart failure. Imaging analysis technique by electron microscopic histopathology and quantitative evaluation method by automatic measurement of chromatin score were established and the severity of human heart failure was evaluated. Regarding the CR9 enhancer discovered by us, the mechanotransduction mechanism through CR9 activation was clarified, making it possible to stratify heart failure exacerbation using CR9-Tg mouse. It was suggested that development of new irreversible assessment index can be developed by expanding this research and carrying out human clinical observation research.

Academic Significance and Societal Importance of the Research Achievements

心不全の可逆性に関する組織学的マーカーとして、細胞核クロマチンスコア計測法を確立することで、エピジェネティック機序が心不全に関与することを示唆した研究である。加えて、心不全病態特異的遺伝子発現を示す代表的遺伝子BNP上流にある病態特異的エンハンサーCR9を同定し、動物モデルにおいてCR9エンハンサー活性を世界で初めて確認した。我々が作成したCR9遺伝子改変マウスは心不全を生体下にモニタリングできる心不全モデル動物である。心不全病態進展機序の解明として学術的に、心不全治療薬剤開発および心毒性有無の検証に利用可能な疾患モデル動物を開発したことから、社会・医療経済的にも意義がある研究となった。

Research Products

• [Journal Article] Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling (2018)
  • Author(s): Tobita T, Nomura S, Fujita T, Morita H, Asano Y, Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M, Fujita K, Naito AT, Furutani Y, Toko H, Harada M, Amiya E, Hatano M, Takimoto E, Shiga T, Nakanishi T, Sakata Y, Ono M, Saito Y, Takashima S, Hagiwara N, Aburatani H, Komuro I.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 20114-20119
  • DOI: 10.1038/s41598-018-20114-9
  • Peer Reviewed / Open Access
• [Journal Article] Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms (2017)
  • Author(s): Kondo H, Maksimova N, Otomo T*,Kato H, Imai A, Asano Y, Kobayashi K, Nojima S, Nakaya A, Hamada Y, Irahara K, Gurinova E, Sukhomyasova A, Nogovicina A, Savvina M, Yoshimori T, Ozono K Sakai N*
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 173-183
  • DOI: 10.1093/hmg/ddw377
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sphingomyelin Phosphodiesterase 3 Enhances Cytodifferentiation of Periodontal Ligament Cells (2017)
  • Author(s): S Miyauchi, J Kitagaki, R Masumoto, A Imai, K Kobayashi, A Nakaya, S Kawai, C Fujihara, Y Asano, M Yamashita, M Yanagita, S Yamada, M Kitamura, S. Murakami
  • Journal Title: J Dent Res Volume: 96 Issue: 3 Pages: 339-46
  • DOI: 10.1177/0022034516677938
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts. (2017)
  • Author(s): Asanuma H, Sanada S, Yoshitomi T, Sasaki H, Takahama H, Ihara M, Takahama H, Shinozaki Y, Mori H, Asakura M, Nakano A, Sugimachi M, Asano Y, Minamino T, Takashima S, Nagasaki Y, Kitakaze M.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 31 Issue: 5-6 Pages: 501-510
  • DOI: 10.1007/s10557-017-6758-6
  • Peer Reviewed / Open Access
• [Journal Article] Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition. (2016)
  • Author(s): Ma J, Luo T, Zeng Z, Fu H, Asano Y, Liao Y, Minamino T, Kitakaze M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34036-34036
  • DOI: 10.1038/srep34036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Putative Association of a Single Nucleotide Polymorphism in GPR126 with Aggressive Periodontitis in a Japanese Population (2016)
  • Author(s): Kitagaki J, Miyauchi S, Asano Y, Imai A, Kawai S, Michikami I, Yamashita M, Yamada S, Kitamura M, Murakami S
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0160765-e0160765
  • DOI: 10.1371/journal.pone.0160765
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA. (2016)
  • Author(s): Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28592-28592
  • DOI: 10.1038/srep28592
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Development of Nucleic Chromatin Measurements as a New Prognostic Marker for Severe Chronic Heart Failure. (2016)
  • Author(s): Kanzaki M, Asano Y, Ishibashi-Ueda H, Oiki E, Nishida T, Asanuma H, Kato H, Oka T, Ohtani T, Tsukamoto O, Higo S, Kioka H, Matsuoka K, Sawa Y, Komuro I, Kitakaze M, Takashima S, Sakata Y.
  • Journal Title: PLoS One. Volume: 11 Issue: 2 Pages: e0148209-e0148209
  • DOI: 10.1371/journal.pone.0148209
  • Peer Reviewed / Open Access
• [Presentation] プレナリーセッション：多層化する循環器ゲノム研究（Multilayered Cardiovascular Genetics） Clinical Application of Whole Exome Sequencing inSinus Bradycardia and a Strategy for Development of aNovel Targeted Therapy (2018)
  • Author(s): 朝野仁裕
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] 教育セッション：ゲノム診療が循環器医に求めるもの (2017)
  • Author(s): 朝野仁裕
  • Organizer: 第123回日本循環器学会近畿地方会
  • Invited
• [Presentation] 特別講演：「次世代シークエンサーから見えてくる循環器疾患の病態」 循環器希少難病に対する疾患ゲノム解析の実際と臨床応用 (2017)
  • Author(s): 朝野仁裕
  • Organizer: 第20回小児心血管分子医学研究会
  • Invited
• [Presentation] BNPエンハンサー領域に着目した新規心毒性評価系の開発 (2017)
  • Author(s): 宮下洋平、朝野仁裕
  • Organizer: Molecular Cardiovascular Metabolic Conference
• [Presentation] De novo BNP enhancer region (CR9) works as the mechanical stress-responsive element of Nppb (2017)
  • Author(s): 宮下洋平、朝野仁裕
  • Organizer: 第1回日本循環器学会基礎研究フォーラム
  • Int'l Joint Research
• [Presentation] 心筋症症例の全エクソームシーケンスによる疾患変異解析（Genetic Analysis for a Cardiomyopathy population with Whole Exome Sequencing） (2017)
  • Author(s): 多久和綾子、朝野仁裕
  • Organizer: 第62回日本人類遺伝学会
• [Presentation] 心筋症のエクソーム解析による原因変異検索 (2017)
  • Author(s): 多久和綾子、朝野仁裕
  • Organizer: 第40回 日本分子生物学会年会
• [Presentation] 難治性遺伝性循環器疾患における全エクソーム解析と家系症例に対する臨床遺伝子診断の試み (2016)
  • Author(s): 朝野仁裕
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-08
  • Int'l Joint Research
• [Presentation] 教育セッション（６）「臨床医が学ぶ基礎医学講座」 「疾患ゲノム解析の進化と臨床への応用」 (2015)
  • Author(s): 朝野仁裕
  • Organizer: 第19回日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-24
  • Invited
• [Presentation] 心筋症の遺伝子・分子医学・基礎と臨床「遺伝性心筋症における新たなゲノム情報解析による変異同定法の開発」 (2015)
  • Author(s): 朝野仁裕
  • Organizer: 第１回心筋症研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-04
  • Invited
• [Book] 「ここが知りたい、強心薬のさじ加減」 急性心不全：４章：「強心薬の効果が十分でない時の対応」 (2016)
  • Author(s): 朝野仁裕
  • Publisher: 中外医学社
• [Book] 「重症心不全の患者さんが来ました」 第１０章：「遺伝子」 (2016)
  • Author(s): 朝野仁裕
  • Publisher: 中外医学社
• [Book] 最新医学 別冊 診断と治療のABC 「心不全」 第２章 病態・病態生理、心筋症の原因遺伝子 (2015)
  • Author(s): 朝野仁裕
  • Publisher: 最新医学社