| Project/Area Number |
17H02092
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Biomedical engineering/Biomaterial science and engineering
|
|---|
| Research Institution | Kawasaki Medical School |
|---|
Principal Investigator |
Hashimoto Ken 川崎医科大学, 医学部, 准教授 (80341080)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
毛利 聡 川崎医科大学, 医学部, 教授 (00294413)
花島 章 川崎医科大学, 医学部, 講師 (70572981)
氏原 嘉洋 名古屋工業大学, 工学(系)研究科(研究院), 准教授 (80610021)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
|
|---|
| Keywords | 心筋細胞 / 分裂・再生 / Fam64a / 酸素環境 / 概日リズム / 不整脈 / APC/C / 心筋再生 / 心筋分裂 / 分裂 / 再生 / 酸素 / 生物・生体工学 / 生理学 / 循環器・高血圧 |
|---|
| Outline of Final Research Achievements |
Fetal cardiomyocytes (CMs) actively proliferate to form the primitive heart, but they stop dividing shortly after birth. Therefore, CM regenerative potential upon injury is very limited in adult hearts. We have recently shown the importance of hypoxic in utero environments for active fetal CM proliferation, and identified Fam64a as a fetal-specific CM cell cycle promoter. Here we analyzed CM-specific Fam64a transgenic (TG) mice, which maintained Fam64a expression still after birth, when endogenous expression was rarely detectable. Although improved CM proliferation at neonatal and adult stages was observed in TG mice, they unexpectedly showed age-related cardiac dysfunction with poor survival. Mechanistically, excessive Fam64a in TG mice disrupted normal cardiac electrical activity through perturbing circadian rhythm regulation in CMs, resulting in cardiac dysfunction. It is necessary to prevent the accumulation of Fam64a for successful heart regeneration without cardiac dysfunction.
|
| Academic Significance and Societal Importance of the Research Achievements |
成体期心筋細胞は分裂能を失っており、心不全等で失われた心筋を再生することは出来ない。iPS細胞から作られた心筋は現段階では未熟で、成体心筋の代替としては不十分である。これに対して近年、分裂が活発な胎生期の心筋環境を成体心筋で再現することで再生を目指す戦略が注目されている。本研究では、胎生期心筋の分裂を促進するFam64aを過剰発現するマウスを作製した。本マウスでは期待通り成体期心筋の分裂能の亢進を認めたが、一方で過剰蓄積したFam64aが律動的な心筋の電気活動を障害し、加齢と共に心機能が悪化した。今後はFam64aの発現を適切に制御することで過剰蓄積を防止し、心機能悪化を伴わない再生を目指す。
|
