| Project/Area Number |
17K09764
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | Juntendo University |
|---|
Principal Investigator |
Ueno Yuji 順天堂大学, 医学部, 准教授 (00349002)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
|---|
| Keywords | 脳梗塞 / セマフォリン3A / エクソソーム / microRNA / 軸索再生 / 脳虚血 / 機能回復 / マイクログリア / アストロサイト / 脳血管障害 / Semaphorin3A / 初代培養神経細胞 / ラット中大脳動脈閉塞モデル / 脳神経疾患 |
|---|
| Outline of Final Research Achievements |
In rats subjected to MCA occlusion, we administered a Semaphorin 3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated NFH-immunoreactive axons were increased, GFAP-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after MCAO. In cultured neurons, the Semaphorin 3A inhibitor decreased Rnd1, increased R-Ras, which phosphorylates Akt and GSK-3β, selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated NFH-immunoreactive axons after OGD. In cultured astrocytes, the Semaphorin 3A inhibitor suppressed activation of astrocytes induced by OGD. Exosomes secreted from ischemic astrocytes treated with the Semaphorin 3A inhibitor regulated expression of microRNAs, and further promoted axonal elongation together with an increase of ptgds. GSK-3β+ and PTGDS+ neurons were robustly increased after treatment with the Semaphorin 3A inhibitor in the peri-infarct area.
|
| Academic Significance and Societal Importance of the Research Achievements |
我々は軸索伸長阻害因子である Semaphorin3Aに着目し、脳梗塞再生治療の新たな分子標的として見出した。Semaphorin3A阻害薬は、脳梗塞後の神経細胞内情報伝達系を制御し、アストロサイトの活性化を抑制、軸索伸展効果を有するエクソソームを分泌する現象がみられた。今日では急性期治療が主体となっている脳梗塞治療において、Semaphorin3A阻害薬は慢性期神経再生や機能回復をターゲットとした脳梗塞新規治療薬となる可能性がある。脳梗塞患者のQOLを高めるという高い社会的ニーズに答えるのみならず、脳卒中医療を大きく変革させる治療薬となる可能性がある。
|
