A Transient Up-regulation of Retinoic Acid Signaling Induces Cell Cycle Arrest in Neonatal Mammalian Heart
| Project/Area Number |
17K09573
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Cardiovascular medicine
|
|---|
| Research Institution | Nagoya University |
|---|
Principal Investigator |
Unno Kazumasa 名古屋大学, 医学系研究科, 招へい教員 (40709119)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
|
|---|
| Keywords | 心筋細胞 / 細胞分裂 / 核内受容体 / レチノイン酸 / 低酸素誘導因子 / エピゲノム修飾 / 低酸素応答 / エピゲノム / 心筋分裂 / 生後心筋分化 / 心筋細胞分裂 |
|---|
| Outline of Final Research Achievements |
Several lines of evidence suggest that mammalian cardiomyocytes lose their ability of cell division during neonatal period, however, the underling mechanism is remained yet to be elucidated. We hypothesized that nuclear receptors play a role in the process of cell cycle arrest in neonatal cardiomyocyte. We found that all trans retinoic acid, a ligand of retinoic acid (RA) receptors,inhibits the cell cycle of cardiomyocyte. Moreover, Aldh1a2, a rate limiting enzyme of RA biosynthesis, is transiently upregulated peaking at postnatal day 6 in mouse heart. We also found that the gene expression of Aldh1a2 is under control of oxygen concentration through Hif1a, hypoxia inducible factor 1a. Accordingly, we conclude that increased tissue oxygen concentration degrades Hif1a which is negatively regulating the gene expression of Aldh1a2. Stimulated RA receptors,modulate cell cycle related gene expressions including Cyclin B1 or Cyclin D1, thereby inhibit cell cycle progression.
|
| Academic Significance and Societal Importance of the Research Achievements |
ヒトを含む哺乳類の心筋細胞は分裂能が無く、心筋梗塞などで一旦その数が減ると再生されないと考えられてきた。しかし、最近の報告によると哺乳類の心筋細胞もその数は限られているが分裂能を有していることが明らかになってきた。この心筋細胞の分裂効率を上昇させることができれば残存心筋から心機能を回復するだけの心筋細胞を再生させることができるかもしれない。
研究代表者らの今回の研究は、心筋細胞の分裂能喪失という新生児期に起こる現象のメカニズムを検討することで、将来的に残存心筋の分裂能を再開させ心筋再生を治療応用できるレベルまで高めることを実現する端緒となる基礎研究であると考えられる。
|
Report
(4 results)
Research Products
(7 results)
-
-
[Journal Article] Alteration in ventricular pressure stimulates cardiac repair and remodeling2019
Author(s)
Unno Kazumasa、Oikonomopoulos Angelos、Fujikawa Yusuke、Okuno Yusuke、Narita Singo、Kato Tomohiro、Hayashida Ryo、Kondo Kazuhisa、Shibata Rei、Murohara Toyoaki、Yang Yanfei、Dangwal Seema、Sereti Konstantina-Ioanna、Yiling Qiu、Johnson Kory、Jha Alokkumar、Sosnovik David E.、Fann Yang、Liao Ronglih
-
Journal Title
Journal of Molecular and Cellular Cardiology
Volume: 133
Pages: 174-187
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
-
[Journal Article] Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin.2019
Author(s)
Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, Amano M, Kato K, Tsuda T, Eguchi S, Ishihama S, Mori Y, Yura Y, Yoshida T, Unno K, Okumura T, Ishii H, Shimizu Y, Bando YK, Ohashi K, Ouchi N, Enomoto A, Offermanns S, Kaibuchi K, Murohara T.
-
Journal Title
Circulation.
Volume: 140
Issue: 21
Pages: 1737-1752
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
