| Project/Area Number |
18K08534
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
|
|---|
| Research Institution | National Center for Global Health and Medicine |
|---|
Principal Investigator |
Mitsushima Masaru 国立研究開発法人国立国際医療研究センター, その他部局等, 分子代謝制御研究部上級研究員 (40621107)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | 糖尿病 / 肝糖新生 / Dyrk1B / 遺伝子転写 / 遺伝子転写制御 / メタボリックシンドローム / シグナル伝達 |
|---|
| Outline of Final Research Achievements |
In this study, we identified Dyrk1B as a binding partner of CITED2 as well as novel regulator of hepatic gluconeogenesis through the gene expression of several gluconeogenic enzymes. Dyrk1B directly phosphorylates GCN5 and PGC-1α, which result in the activation of HAT or co-activation, respectively. In addition, Dyrk1B is directly phosphorylated by PKA, which suppresses the kinase activity of Dyrk1B. We also found that the expression of Dyrk1B in the mouse liver is suppressed by postprandial insulin. In dietary induced obesity (DIO) mice, model for type 2 diabetes, the expression of Dyrk1B is up-regulated because of their insulin resistance and the suppression of exceeded expression of Dyrk1B in the liver resulted in the lowered blood glucose level during fasting. Altogether, we propose that Dyrk1B is a novel regulator of hepatic gluconeogenesis as well as therapeutic target for type 2 diabetes.
|
| Academic Significance and Societal Importance of the Research Achievements |
Dyrk1Bは近年その遺伝子多型がメタボリックシンドロームの早期発症への関与が報告されているが、その聖書機構はほとんど解明されていない。本研究ではDyrk1Bが我々の研究部で独自に見出してきた肝糖新生制御GCN5-CITED2-PKAモジュールの相互作用因子としてDyrk1Bを同定し、本モジュール内でGCN5を直接リン酸化しモジュールの活性を調節すると同時に、PGC-1αもリン酸化して活性化することで肝糖新生を制御していることを明らかにした。2型糖尿病モデルのDIOマウスでDyrk1Bを抑制すると絶食時血糖が低下したことから、Dyrk1Bは2型糖尿病治療標的にもなり得ると考えらる。
|
