| Project/Area Number |
16K07043
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Nerve anatomy/Neuropathology
|
|---|
| Research Institution | Meiji Pharmaceutical University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
紀 嘉浩 明治薬科大学, 薬学部, 准教授 (80415140)
|
|---|
| Research Collaborator |
Yanaizu Motoaki
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | 那須・ハコラ病 / DAP12 / TREM2 / ミクログリア / オリゴデンドロサイト / 白質脳症 / gp91phox / snRNAs / Nasu-Hakola disease / leukoencephalopathy / microglia / oligodendrocytes / ROS / アルツハイマー病 / 遺伝子診断 / 免疫組織化学 / シグナル伝達 / reactive oxygen species / 那須ハコラ病 / 脳分子病態 |
|---|
| Outline of Final Research Achievements |
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TREM2 or DAP12, characterized by multiple bone cysts and early-onset dementia due to leukoencephalopathy. TREM2-DAP12 forms a receptor/adapter complex expressed exclusively on microglia (MG) or osteoclasts. In the present study, we analyze the activation status of MG by immunohistochemistry in NHD brains, and design a therapeutic molecule to inhibit a splicing mutation of TREM2. First, we identified the expression of p22phox and gp91phox. The latter was up-regulated in NHD brains. Second, by analysis on ProtoArray protein microarray with TREM2-V5 probe, we identified cardiolipin as a putative TREM2 ligand. Third, we designed several U1 small nuclear RNAs (snRNAs) that enhance exon 3 inclusion in TREM2 intron 3 mutation c.482+2T>C. In conclusion, oxidative stress caused by MG induces extensive oligodendrocyte (OL) damage.
|
| Academic Significance and Societal Importance of the Research Achievements |
那須・ハコラ病(NHD)は多発性骨嚢胞と白質脳症による認知症を主徴とする常染色体劣性遺伝疾患で、希少疾患で治療法はない。NHDではDAP12遺伝子またはTREM2遺伝子に変異を認める。これらはミクログリア(MG)特異的に発現し、白質脳症の原因としてミクログリア(MG)の機能障害が考えられる。本研究ではNHD脳でMGの活性化状態を解析した。その結果、gp91phoxの発現上昇を初めて発見した。またTREM2 intron 3 mutation c.482+2T>C変異で、exon 3の含有を促進するU1 small nuclear RNAsのデザインに成功し、NHDの治療に道を開いた。
|
