Development of basic technology for intractable and rare diseases
| Project/Area Number |
19K22601
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 52:General internal medicine and related fields
|
|---|
| Research Institution | University of the Ryukyus (2021)
Yokohama City University (2019-2020) |
|---|
Principal Investigator |
YAMASHITA AKIO 琉球大学, 医学(系)研究科(研究院), 教授 (20405020)
|
|---|
| Project Period (FY) |
2019-06-28 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
|
|---|
| Keywords | mRNA分解 / mRNA翻訳 / ナンセンス変異 / mRNA監視機構 / 嚢胞性線維症 / nonsense mutation / mRNA decay / モデルマウス / SMG1 |
|---|
| Outline of Research at the Start |
本研究では、NMD阻害による遺伝性疾患治療の可能性について細胞、個体レベルで検討・検証することを目的とする。初期対象疾患として、嚢胞性線維症患者由来細胞を用い、独自のSMG1阻害剤、リドスルー剤、CFTR安定化剤（VX-770）による遺伝性疾患治療のin vitroレベルでのPOCを取得する。同時に、独自に樹立した嚢胞性線維症モデルマウスを用いて、リドスルー剤、CFTR安定化剤（VX-770）、SMG1阻害剤投与による遺伝性疾患治療のin vivoレベルでのPOCを取得する。これらの解析により、希少遺伝性疾患治療のin vitro、in vivoレベルでのPOCを取得し研究を加速させる。
|
| Outline of Final Research Achievements |
Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In present study, we identified several approved drugs which can repress NMD activity in cells. These drugs are previously not linked with NMD.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究で得られた、複数のmRNA監視機構を阻害する臨床薬は、これまで、NMDとの関わりがわかっていなかった化合物であり、培養細胞レベルではあるが、新たなNMD阻害法の発見となった。このmRNA監視機構阻害法は、臨床で用いられる薬剤による物であるため、安全性などの情報が得られている。今後、動物モデルを用いたmRNA監視機構抑制の検証後、早期に人における応用へつなげられる事が期待される。
|
Report
(4 results)
Research Products
(23 results)
-
-
-
-
-
-
-
-
-
-
[Journal Article] Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice2020
Author(s)
Wakui H, Yamaji T, Azushima K, Uneda K, Haruhara K, Nakamura A, Ohki K, Kinguchi S, Kobayashi R, Urate S, Suzuki T, Kamimura D, Minegishi S, Ishigami T, Kanaoka T, Matsuo K, Miyazaki T, Fujikawa T, Yamashita A, Tamura K.
-
Journal Title
Scientific Reports
Volume: 10
Issue: 1
Pages: 1782-1782
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line2019
Author(s)
Yamaji T, Yamashita A, Wakui H, Azushima K, Uneda K, Fujikawa Y, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Ishii T, Yamada T, Urate S, Suzuki T, Abe E, Tanaka S, Kamimura D, Ishigami T, Toya Y, Takahashi H, Tamura K.
-
Journal Title
Scientific Reports
Volume: 9
Issue: 1
Pages: 16550-16550
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
[Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation.2019
Author(s)
Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O.
-
Journal Title
Nat Microbiol
Volume: 4
Issue: 9
Pages: 1532-1544
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
[Journal Article] Effects of ATRAP in Renal Proximal Tubules on Angiotensin‐Dependent Hypertension2019
Author(s)
Kinguchi Sho、Wakui Hiromichi、Azushima Kengo、Haruhara Kotaro、Koguchi Tomoyuki、Ohki Kohji、Uneda Kazushi、Matsuda Miyuki、Haku Sona、Yamaji Takahiro、Yamada Takayuki、Kobayashi Ryu、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Fujikawa Tetsuya、Tamura Kouichi
-
Journal Title
Journal of the American Heart Association
Volume: 8
Issue: 8
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
-
[Presentation] PI3 kinase様タンパク質リン酸化酵素SMG1による酸化ストレス依存的なNRF2活性制御機構の解析2019
Author(s)
藤川由美子, 山下暁朗, 大貫 哲男, 鈴木香絵, 青柳杏子, 黒澤瞳, 廣瀬博子, 永井陽子, 上村博司, 吉田稔, 高橋秀尚, 大野 茂男
Organizer
第42回日本分子生物学会年会
Related Report
-
-
