| Project/Area Number |
17590736
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Okayama University |
|---|
Principal Investigator |
KUSANO Kengo Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (60314689)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Kazufumi Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Assistant, 大学院医歯薬学総合研究科, 助手 (10335630)
OHE Tohru Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (70263556)
ASAHARA Takayuki Tokai University School of Medicine, Professor, 医学部, 教授 (20246200)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Keywords | sonic hedgehog / angiogenesis / myocardial ischemia / gene therapy / apoptosis / progenitor cell / cytokine / tissue repair / 再生医療 / Sonic Hedgehog / 心筋再生 |
|---|
| Research Abstract |
Sonic hedgehog (Shh) is a critical regulator for organ development in embryogenesis. Recent observations indicate that exogenous administration of Shh protein stimulates interstitial mesenchymal cells to secrete various angiogenic cytokines and indirectly promote angiogenesis in animal model of hindlimb ischemia. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute myocardial ischemia, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryonic life. We found that the hedgehog-signaling pathway is intact even in the post-natal adult heart and can be activated after ischemia. After Shh gene transfer, the hedgehog pathway was upregulated, not only in fibroblasts but also in cardiomyocytes. Human Shh gene therapy preserved left ventricular function in acute myocardial ischemia model by enhancing neovascularization, but also by reducing fibrosis and preventing cardiac apoptosis. Shh also enhanced the contribution of bone marrow derived endothelial progenitor cells to myocardial neovascularization. In cardiac fibroblasts, Shh upregulated various angiogenic cytokines (VEGF, angiopoietin-1, 2), anti-apoptotic cytokines (IGF) and SDF-la, a trafficking chemokine for hematopoietic bone marrow derived progenitor cells. Furthermore, Shh directly induced myocardial proliferation in vivo and in vitro. These data suggest that Shh gene therapy may have significant therapeutic potential in patients with acute and chronic myocardial ischemia by reactivation of an embryonic signaling pathway in the adult heart, which triggers multiple downstream trophic factors to reconstitute the regenerative response in the adult.
|
