Epigenetic modification in hypertrophied nuclei of the cardiomyocytes and its pathophysiological significance
| Project/Area Number |
16K09509
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Cardiovascular medicine
|
|---|
| Research Institution | Asahi University |
|---|
Principal Investigator |
竹村 元三 朝日大学, 歯学部, 教授 (40283311)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
金森 寛充 岐阜大学, 医学部附属病院, 講師 (20456502)
岡田 英志 岐阜大学, 医学部附属病院, 講師 (30402176)
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
|
|---|
| Keywords | エピジェネティクス / 心不全 / 心肥大 / 心筋細胞 / 肥大核 / ＤＮＡメチル化 / 超微形態 / 核肥大 / DNAメチル化 |
|---|
| Outline of Annual Research Achievements |
本研究では心筋細胞の肥大核におけるＤＮＡメチル化をまずヒトの心筋生検標本にて検討し新機能など病態との関連を調べさらに動物の心不全モデルにてＤＮＡメチル化阻害薬によるエピジェネティック介入を行い心不全に対する治療の可能性を探索することを目的とした。
まずヒト心不全における心筋細胞核肥大びおいてエピジェネティック変化（ＤＮＡメチル化の頻度と核内分布）を検討し心機能・心筋病理など病態との関連を調べた。すなわち心不全を呈する拡張型心筋症７５症例、心不全のないコントロール２０症例の心筋生検標本を用いて5-methylcytosine（メチル化ＤＮＡ）の免疫染色ならびに免疫電顕を施行したところメチル化ＤＮＡ陽性細胞の頻度が心不全で有意に増加していたが、増加がみられたのは心筋細胞に限定されておりその他の非心筋細胞においては心不全とコントロールで差が見られなかった。免疫電顕ではメチル化ＤＮＡの局在はヘテロクロマチンに集中していた。さらにメチル化ＤＮＡ陽性心筋細胞の頻度は左室リモデリングの程度と正の相関を左室機能と負の相関を示した。
次に動物実験にてＤＮＡメチル化の心不全における病態生理学的意義について調べた。モデル動物としてδ-Sarcogycan欠損心筋症マウスを用いた。本動物は繁殖力が弱く実験開始に手間取ったものの最近ようやくＤＮＡメチル化阻害薬投与による生存率の変化を調べることができた。10週令のマウスに5-azacytidine 1 mg/kg/dayを投与したところ、６週後の生存率は無治療群では69％(11/16)に対し治療群で100％(4/4)と有意差は無いものの上昇した。現在治療群の動物数を増やしかつ心筋組織を病理学的並びに生化学的に解析中である。
|
Report
(3 results)
Research Products
(28 results)
-
-
-
-
[Journal Article] Liver fibrogenesis marker, 7S domain of collagen type IV in patients with acutely decompensated heart failure: Correlates, prognostic value and time course.2017
Author(s)
Nagao K, Hayashi F, Inada T, Yukawa H, Morimoto T, Tanaka M, Shimamura K, Makita T, Tamura A, Takemura T, Kimura T, Sato Y, Ito H.
-
Journal Title
Int J Cardiol.
Volume: 236
Pages: 483-487
DOI
Related Report
Peer Reviewed
-
-
[Journal Article] Three-dimensional ultrastructure of capillary endothelial glycocalyx under normal and experimental endotoxemic conditions2017
Author(s)
Okada H, Takemura G, Suzuki K, Oda K, Takada C, Hotta Y, Miyazaki N, Tsujimoto A, Muraki I, Ando Y, Zaikokuji R, Matsumoto A, Kitagaki H, Tamaoki Y, Usui T, Doi T, Yoshida T, Yoshida S, Ushikoshi H, Toyoda I, Ogura S.
-
Journal Title
Critical Care
Volume: 26
Pages: 261-261
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Mitochondrial deformity confined to a single cardiomyocyte in human endomyocardial biopsy specimens: Report of 4 cases.2017
Author(s)
Takemura G, Kanmori H, Okada H, Tsujimoto A, Miyazaki N, Miyata S, Ohta H, Kawase Y, Ono M, Mochizuki M, Kobayashi S, Onoue K, Nakano T, Sakaguchi Y, Matsuo H, Yano M, Saito Y.
-
Journal Title
J Cardiol Cases.
Volume: 16
Pages: 178-182
Related Report
Peer Reviewed
-
-
[Journal Article] Non-invasive tissue characterization of lung tumors using integrated backscatter intravascular ultrasound: An ex vivo comparative study with pathological diagnosis.2016
Author(s)
Ito F, Kawasaki M, Ohno Y, Toyoshi S, Morishita M, Kaito D, Yanase K, Funaguchi N, Asano M, Endo J, Mori H, Kobayashi K, Nishigaki K, Miyazaki T, Takemura G, Minatoguchi S.
-
Journal Title
Chest
Volume: 149
Pages: 1276-1284
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
-
[Journal Article] Urinary 8-hydroxy-2’-deoxyguanosine as a biomarker of oxidative stress for prediction of cardiovascular-related death in patients with cardiac sarcoidosis.2016
Author(s)
Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
-
Journal Title
International Journal of Cardiology.
Volume: 17
Pages: 206-213
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
-
-
-
[Presentation] In Situ Nuclear DNA Methylation in Human Failing Hearts with Dilated Cardiomyopathy.2019
Author(s)
Watanabe T, Okada H, Kanamori H, Miyazaki N, Tsujimoto A, Takada C, Suzuki K, Nawa T, Tanaka T, Kawasaki M, Ogura S, Hotta Y, Fujiwara T, Fujiwara H, Takemura G.
Organizer
第83回日本循環器学会学術集会
Related Report
-
[Presentation] In situ nuclear DNA methylation in human failing hearts with dilated cardiomyopathy.2018
Author(s)
Watanabe T, Okada H, Kanamori H, Miyazaki N, Tsujimoto A, Nawa T, Tanaka T, Kawasaki M, Fujiwara T, Fujiwara H, Takemura G.
Organizer
2018 Congress of European Society of Cardiology
Related Report
Int'l Joint Research
-
-
-
-
-
-
[Presentation] Neutrophil Elastase Plays a Pivotal Role in Sepsis-induced Myocardial Dysfunction.2017
Author(s)
Suzuki K, Okada H, Takemura G, Yamaji F, Takada C, Oda K, Hotta Y, Miyazaki N, Doi T, Yoshida T, Yoshida S, Ushikoshi H, Ogura S.
Organizer
2017 Congress of American Heart Association
Related Report
Int'l Joint Research
-
[Presentation] Metformin Displays Cardioprotection in δ-sarcoglycan Deficiency Induced Cardiomyopathy Through Autophagic Activation via AMPK-mTOR Pathway.2017
Author(s)
Kanamori H, Naruse G, Yoshida A, Minatoguchi S, Komaki H, Baba S, Yamada Y, Mikami A, Kawasaki M, Nishigaki K, Takemura G, Minatoguchi S.
Organizer
2017 Congress of American Heart Association
Related Report
Int'l Joint Research
-
-
-
-
-
-
-
