Identification of Novel Molecular Targets and Drug Development by Genomic and Multilayer-Omics Analysis of Hereditary Cardiomyopathies
| Project/Area Number |
19H03652
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Osaka University |
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Principal Investigator |
Asano Yoshihiro 大阪大学, 医学系研究科, 特任准教授(常勤) (60527670)
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| Co-Investigator(Kenkyū-buntansha) |
宮下 洋平 大阪大学, 医学系研究科, 助教 (60816312)
木岡 秀隆 大阪大学, 医学系研究科, 助教 (70642099)
塚本 蔵 大阪大学, 生命機能研究科, 准教授 (80589151)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Keywords | 心筋症 / ゲノムデータベース構築 / オミックス研究 / 創薬治療法開発 / ゲノム / オミックス / 創薬 / 創薬開発 / 新規治療薬開発 / 新規治療法開発 |
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| Outline of Research at the Start |
遺伝性心筋症はさまざまな遺伝子の上に存在する多くの変異が原因に成り得ると考えられている。しかし十分明らかとはなっておらず、疾患の正確な分類とそれに対応する治療法の開発はまだ途上にある。独自に開発した遺伝性心筋症ゲノム変異データベースを用いて、そこから同定される遺伝性心筋症および心不全に関する５つの分子標的に対して、関連する類似変異の機能評価を行うともに、創薬研究の観点から新たな原因分子探索も行い、それらの生理活性の評価系を構築してそれに基づく心筋症治療薬創出研究基盤を構築する。
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| Outline of Final Research Achievements |
For drug discovery research and development related to hereditary cardiomyopathy and heart failure, we have identified the cause of the disease, searched for novel molecular targets, and established a research platform for the creation of cardiomyopathy drugs based on a bioactivity evaluation system. In addition to developing an integrated database of clinical and genomic variant information, we identified that homozygous truncating pathogenic variants in the gene encoding Bcl-2 associated athanogene (BAG) co-chaperone 5 (BAG5) among five patients with inherited dilated cardiomyopathy. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an AAV-BAG5 gene could fully ameliorate these DCM phenotypes.
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| Academic Significance and Societal Importance of the Research Achievements |
心筋収縮機構および恒常性に関与する新規遺伝子の同定を行うため、次世代ゲノム解析技術（全エクソーム解析、全ゲノム解析、構造解析、横断オミックス解析）を応用し、疾患バリアントの同定を行い、新規心筋症原因遺伝子を同定した。結果をもとに新規創薬標的の分子探索を実施し、心臓特異的な疾患原因分子の病態機序に立脚した効率的な研究基盤を構築し、大規模計算リソースを用いた情報解析を実施した。その結果、疾患ゲノムバリアントデータベースを構築した。その他にも機能未知の心筋症分子探索から疾患機序を同定し、その機能評価を行い、治療標的として導出した。
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Report
(3 results)
Research Products
(37 results)
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[Journal Article] The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression2021
Author(s)
Miyashita Y, Tsukamoto O, Matsuoka K, Kamikubo K, Kuramoto Y, Fu HY, Tsubota T, Hasuike H, Takayama T, Ito H, Hitsumoto T, Okamoto C, Kioka H, Oya R, Shinomiya H, Hakui H, Shintani Y, Kato H, Kitakaze M, Sakata Y, Asano Y, Takashima S
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Journal Title
The FASEB Journal
Volume: 35
Issue: 4
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome.2020
Author(s)
Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
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Journal Title
FASEB Journal
Volume: 34
Issue: 5
Pages: 6399-6417
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019
Author(s)
Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
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Journal Title
Circulation
Volume: In press
Issue: 18
Pages: 2157-2169
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy2019
Author(s)
Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
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Journal Title
ESC Heart Fail
Volume: 6
Issue: 2
Pages: 06-415
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese2019
Author(s)
Ogawa, Kotaro; Okuno, Tatsusada; Hosomichi, Kazuyoshi; Hosokawa, Akiko; Hirata, Jun; Suzuki, Ken; Sakaue, Saori; Kinoshita, Makoto; Asano, Yoshihiro; Miyamoto, Katsuichi
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Journal Title
Journal of neuroinflammation
Volume: 16
Issue: 1
Pages: 162-162
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs.2019
Author(s)
Asanuma H, Chung H, Ito S, Min KD, Ihara M, Takahama H, Funayama M, Imazu M, Fukuda H, Ogai A, Asano Y, Minamino T, Takashima S, Morita T, Sugimachi M, Asakura M, Kitakaze M.
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Journal Title
Cardiovasc Drugs Ther.
Volume: 33
Issue: 3
Pages: 277-286
DOI
Related Report
Peer Reviewed
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