| Project/Area Number |
16H02660
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | University of Tsukuba |
|---|
Principal Investigator |
Chiba Shigeru 筑波大学, 医学医療系, 教授 (60212049)
|
|---|
| Research Collaborator |
Kato Takayasu
Nguyen Bich Tran
Hattori Keichiro
Fujisawa Manabu
Fukumoto Kota
Tanzima Nuhat Sharna
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000)
Fiscal Year 2018: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2017: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2016: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
|
|---|
| Keywords | 血管免疫芽球性T細胞リンパ腫 / RHOA / TET2 / VAV1 / 治療標的 / がん / ゲノム / シグナル伝達 / 血液がん / 悪性リンパ腫 / 癌 / 遺伝子 |
|---|
| Outline of Final Research Achievements |
We screened a protein that specifically bound to a previously identified angioimmunoblastic T-cell lymphoma (AITL)-specific RHOA(G17V) mutant, and identified VAV1, a signaling protein. By the binding, VAV1 tyrosine phosphorylation was enhanced and T cell receptor downstream signaling was strengthened. We then showed that dasatinib, a commercially available tyrosine kinase inhibitor, suppressed VAV1 phosphorylation and T cell receptor downstream signals. We also observed that Tet2 gene disruption and RHOA(G17V) expression, mimicking the AITL genome, developed AITL-like T-cell lymphoma in mice, and this tumor responded to dasatinib. The survival of the tumor-bearing recipient mice was prolonged by dasatinib administration.
|
| Academic Significance and Societal Importance of the Research Achievements |
研究代表者らが世界的に高い競争力をもつ血管免疫芽球性T細胞リンパ腫(AITL)について、病態解明と診断・治療法開発を目指した。遺伝子変異の同定に基づいて申請した診断法特許が2018年に成立し検査会社が商品化した。一方、変異蛋白質に特異的に結合する蛋白質の同定を手がかりに、この蛋白質をリン酸化する酵素が治療標的になることを見出し、マウスで作製したAITLモデルを用いて、市販されているチロシンキナーゼ阻害剤が有効であることを示した。この成果に基づいて臨床試験を計画している。期待通りの結果が得られれば、既存薬の適応拡大に繋がり、AITLの新規治療薬として大きな意義をもつ。
|
