| Project/Area Number |
24659540
|
|---|
| Research Category |
Grant-in-Aid for Challenging Exploratory Research
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Psychiatric science
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YAMASHIMA Tetsumori 金沢大学, 医学系, 准教授 (60135077)
|
|---|
| Project Period (FY) |
2012-04-01 – 2015-03-31
|
| Project Status |
Completed (Fiscal Year 2014)
|
| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
|---|
| Keywords | 認知症 / 神経細胞死 / リソソーム / Hsp70.1 / カルボニル化 / カルパイン / カテプシン / ビスモノアシルグリセロフォスフェート / オートファジー / サル / 海馬 / アルツハイマー病 / ビス(モノアシルグリセロ)リン酸 / 酸性スフィンゴミエリナーゼ / プロテオミクス / ヒドロキシノネナール / 酸化ストレス |
|---|
| Outline of Final Research Achievements |
Using the monkey experimental paradigm, previously we reported that calpain-mediated cleavage of oxidized Hsp70.1 causes neurodegeneration in the hippocampal CA1 sector. However, the molecular mechanisms of the lysosomal destabilization/stabilization have not been elucidated. To elucidate whether regulation of lysosomal ASM could affect the neuronal fate, we analyzed Hsp70.1-BMP binding and ASM activity. We showed that Hsp70.1 being localized at the lysosomal membrane, lysosomal lipid BMP levels, and the lipid binding domain of Hsp70.1 are crucial for Hsp70.1- BMP binding. Calpain activation and a concomitant decrease in the lysosomal membrane localization of Hsp70.1 and BMP levels may diminish Hsp70.1-BMP binding, resulting in decreased ASM activity and lysosomal rupture with leakage of cathepsin B into the cytosol. Regulation of ASM activation in vivo by Hsp70.1-BMP affects lysosomal stability and neuronal survival or death after ischemia/reperfusion.
|
