2021 Fiscal Year Final Research Report
Understanding the role of necroptosis in hematopoietic stem cell aging and malignant transformation
Project/Area Number |
20K17395
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | The University of Tokyo |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2022-03-31
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Keywords | 造血幹細胞 / ネクロプトーシス / MLKL / 慢性炎症 / 老化 / 骨髄異形成症候群 / ダメージ関連分子パターン / ミトコンドリア |
Outline of Final Research Achievements |
Age-related functional decline in hematopoietic stem cells (HSCs) is one of the main reasons why the hematopoietic system ages. In this study, we investigated the role of necroptosis, a form of programmed necrosis whose molecular machinery has recently been identified, in HSC functional decline upon inflammation and aging. By analyzing mutant mice deficient for the necroptosis effector MLKL, we found that activation of MLKL drives age-related functional decline in HSCs and disease progression of myelodysplastic syndrome (MDS). Our results identify MLKL as a key mediator of age-related functional attrition in HSCs and ineffective hematopoiesis in MDS, and pave the way for developing new strategies to control aging and age-related diseases in the hematopoietic system.
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Free Research Field |
幹細胞医学
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Academic Significance and Societal Importance of the Research Achievements |
加齢とともに造血幹細胞の機能が低下する仕組みについてはこれまで不明な点が多かったが、本研究によってその分子メカニズムの一端が明らかになった。ネクロプトーシス経路を標的とすることで造血幹細胞の加齢性変化を抑制できれば、造血組織の老化や加齢関連疾患の進行を制御する新しい治療法の開発につながる可能性がある。
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