| Project/Area Number |
16K09705
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | Kindai University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
西郷 和真 近畿大学, 理工学部, 准教授 (50319688)
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | リン酸化阻害剤 / 筋萎縮性側索硬化症 / ERBB4 / ALS / 治療薬開発 / 抗がん剤 / iPS細胞 / 脳神経疾患 |
|---|
| Outline of Final Research Achievements |
This study was aimed to clarify the pathomechanism of amyotrophic lateral sclerosis (ALS) via an ERBB4-related kinase pathway and the effectiveness of anti-cancer kinase inhibitors, using ALS-patient-derived induced pluripotent stem (iPS) cells and cultured neuronal SH-SY5Ycells. In SH-SY5Y cells expressing wild-type (WT) and mutant ERBB4, subcellular localization did not differ between WT and mutant proteins. Most mutants were unstable, but kinase activities varied considerably between mutants. Anti-cancer drugs reduced phosphorylation of ERBB4, but exhibited cellular toxicity. The maintenance of regular neurons induced from patient-derived iPS cells were difficult, but rapamycin and retinoic acid reduced cell death. Motor neurons from patient-derived iPS cells were unstable during motor neuron induction.
|
| Academic Significance and Societal Importance of the Research Achievements |
変異ERBB4蛋白の性質、すなわち、不安定性あるいはリン酸化低下が示され、機能低下が示唆された。一方、強制発現により、細胞が酸化ストレスへ脆弱となる傾向が判明した。別のALS原因蛋白SOD1のように機能低下と毒性獲得の両面から研究を進める必要があると考えられる。今回用いた抗がん剤は、リン酸化を抑制することから、いくつかの変異には逆効果である可能性がある。iPS細胞を用いた結果からは、ラパマイシンやレチノイン酸による部分的細胞死抑制効果が認められ、ERBB4自身のリン酸化カスケードそのものでなく、別の機序も考える必要がある。
|
