| Project/Area Number |
15K15488
|
|---|
| Research Category |
Grant-in-Aid for Challenging Exploratory Research
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Digestive surgery
|
|---|
| Research Institution | University of Tsukuba |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
柳川 徹 筑波大学, 医学医療系, 准教授 (10312852)
蕨 栄治 筑波大学, 医学医療系, 講師 (70396612)
正田 純一 筑波大学, 医学医療系, 教授 (90241827)
|
|---|
| Co-Investigator(Renkei-kenkyūsha) |
YAMAMOTO Masayuki 東北大学, 医学系研究科, 教授 (50166823)
|
|---|
| Project Period (FY) |
2015-04-01 – 2017-03-31
|
| Project Status |
Completed (Fiscal Year 2016)
|
| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
|---|
| Keywords | 生活習慣病 / 臓器レスキューマウス / 脂肪性肝炎 / 非アルコール性脂肪性肝疾患 / 肝癌 / 遺伝子改変マウス / 腸内細菌 / 肥満 / 転写因子 / 遺伝子レスキューマウス / 肝発癌 |
|---|
| Outline of Final Research Achievements |
We generated Sqstm1 and Nrf2 double knockout (DKO) mice and demonstrated that these DKO mice developed mature-onset steatohepatitis. We revealed the mechanism for the development of steatohepatitis in DKO mice as follows: (1) Deficiency of Nrf2 led to hypersensitivity to endotoxin of Kupffer cells and resulted in inflammatory response in the DKO livers. (2) Acceleration of intestinal permeability caused by down-regulation of Zo-1 and Claudin1 in Nrf2 deficiency and increased endotoxin from intestinal microbiota by Sqstm1 deficiency led to an overload of serum endotoxin. (3) These hyper-endotoxemia drove inflammatory signaling in livers directly, and also led to inflammation of adipose tissue. (4) These enhanced inflammatory signaling could cause progression of steatohepatitis in DKO livers. We plan to compare DKO and Nrf2 gene rescued mice, and research the detail of the mechanism for development of NASH and the contribution of each organ in the near future.
|
