| Project/Area Number |
17K09932
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kagoshima University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
原 博満 鹿児島大学, 医歯学域医学系, 教授 (20392079)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 成人T細胞白血病・リンパ腫 / 機能獲得型変異 / CARD11 / 結晶構造 / RLTPR / ATL / 成人T細胞白血病リンパ腫 / 血液腫瘍学 |
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| Outline of Final Research Achievements |
Exome analaysis using 47 patients's sample with adult T cell leukemia/lymphoma was performed and identified novel recurrent mutation, RLTPR Q575E. RLTPR Q575E is found to activate NFkB pathway and co-precipitated with CARD11, a central molecule in NFkB activation. RLTPR is also found to directly interact with Tax, a HTLV-1 derived oncogene. CARD11 gain-of-function knock-in mouse did not form lymphoma even after 3-year observation period but showed increased levels of activated T lymphocytes, regulatory T cells, mature B lymphocytes. Aiming at developing novel CARD11 inhibitor, crystal structure analysis of CARD11 is under investigation. This project is supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED.
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| Academic Significance and Societal Importance of the Research Achievements |
成人T細胞白血病・リンパ腫（ATL)は既存の治療法では満足のいく治療成績が得られていない。そこで最近明らかになった遺伝子変異情報を元にした治療法の開発を目指すための基盤研究を行った。追加で行った遺伝子変異解析ではATLにおいて腫瘍維持に作用している可能性のある新しい遺伝子変異を同定できた。一方約3割のATL症例で有するCARD11の変異について、CARD11の会合阻害剤の開発を目指した。CARD11の結晶構造解析を行うことで創薬等先端技術支援基盤プラットフォーム（BINDS）の支援のとも、活性化の中心であるSH3ドメインとGUKドメインの会合阻害剤の同定を目指す。
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