| Project/Area Number |
18K06892
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 48030:Pharmacology-related
|
|---|
| Research Institution | Yamaguchi University |
|---|
Principal Investigator |
Honda Takeshi 山口大学, 大学院医学系研究科, 講師 (30457311)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
酒井 大樹 山口大学, 大学院医学系研究科, 助教 (40464367)
乾 誠 山口大学, その他部局等, 名誉教授 (70223237)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | 心筋細胞 / 心不全 / ペプチド医薬 / 細胞内導入 / ペプチド / ホスホランバン / 環状ペプチド |
|---|
| Outline of Final Research Achievements |
The function of Ca2+ pump (SERCA) expressed in the cardiac sarcoplasmic reticulum (CSR) is severely impaired in heart failure. Suppressing the function of phospholamban (PLN) that expressed in the CSR and inhibits SERCA activity, improves heart failure by increasing the SERCA activity. Targeting PLN-mediated inhibition of SERCA has been highlighted as a potential approach for the treatment of heart failure, but no useful drugs have been found. In this study, we found cyclic peptides that inhibit PLN function through a screening system based on molecular evolution. We have also developed a system to deliver PLN-binding cyclic peptides into cardiomyocytes using our vector molecule that specifically internalizes into cardiomyocytes. PLN-binding peptides internalized into cardiomyocytes by this delivery system enhanced cardiac function. These results indicate that PLN-targeted peptides could be a new model of therapeutic drugs for heart failure.
|
| Academic Significance and Societal Importance of the Research Achievements |
現行の強心薬は細胞外からのCa2+流入を増加するため、SERCA機能の低下した心不全では細胞質内Ca2+濃度の過剰増加（Ca2+過負荷）が起きやすく、毒性が生じやすい。一方、SERCA系のみの増強は、細胞外からのCa2+流入に依存せずに収縮力の増強をもたらす。また、PLNはSERCAと異なり刺激伝導系には発現せず、本研究のようにPLNを標的とすれば、心拍への影響も少ない理想的な心不全治療薬の開発が可能となる。実現すれば急性及び慢性心不全の両方に有効で、現状では移植以外に救命の手段が無い重症心不全の治療法の選択肢にもなり得るため、社会的貢献度は大きいと思われる。
|
