| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Outline of Final Research Achievements |
Pathophysiological regulation and underlying mechanisms of RAGE shedding are scarcely understood. We showed here that in endothelial-specific human RAGE transgenic mice, human sRAGE level was markedly increased following TNFα. In RAGE overexpressed human endothelial cells, TNFα markedly induced RAGE shedding, which was dependent on ADAM10. TNFα transiently induced ATF4, while knockdown of ATF4 abrogated RAGE shedding. Pro-and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other ER components was without an effect. Notably, though the ER stressors induced marked and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding. ATF4 inhibition did not affect TNFα-stimulated MMP9 expression, which was completely dependent on JNK activation, while inhibition of JNK was partially effective to suppress RAGE shedding. Collectively, TNFα induce RAGE shedding in ATF4 dependent manner.
|
