2018 Fiscal Year Final Research Report
Development of basic technology for intractable and rare diseases
| Project/Area Number |
17K19665
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
General internal medicine and related fields
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Research Collaborator |
Usuki Fusako
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| Project Period (FY) |
2017-06-30 – 2019-03-31
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| Keywords | nonsense mutation / mRNA decay / translation / small compound / screening |
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| Outline of Final Research Achievements |
NMD is an mRNA surveillance mechanism that eliminates aberrant mRNAs carrying premature termination codons (PTCs). NMD degrades not only proteins that show dominant-negative function but also aberrant proteins that retain at least some aspect of their normal cell function. If mutant proteins are still functional, the selective inhibition of NMD provides a strategy to ameliorate disease phenotypes in patients with PTC-related conditions. Another strategy to inhibit NMD for the rescue of intractable diseases involves drugs causing translational readthrough. In this project we developed accurate reporter system of NMD and translational readthroug. Using this system, we demonstrated that translational readthrough has little effect on PTC-mRNA decay, NMD inhibition resulted in a synergistic effect on read-through efficiency. We also developed the immortalized cells from Ullrich disease patient and CF model mice with PTC mutation.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、異常終止コドンを生じる遺伝子変異による遺伝性疾患について、NMDを抑制することにより治療するための薬剤開発基盤技術創出に成功した。具体的には、薬剤スクリーニングのための改良型高精度NMD検出技術、in vivo POC取得のための、遺伝性疾患患者由来不死化細胞、嚢胞性線維症PTCマウスである。これらの技術を基に得られる薬剤により、これまで治療法のなかった遺伝性疾患について、異常終止コドンまでのタンパク質が機能を有するものについては治療が可能となることが期待される。また、NMD阻害剤とリードスルー薬を組み合わせることにより、多くの遺伝性疾患についても治療可能となることも期待される。
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