| Project/Area Number |
21K06870
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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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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
Huang Gang 熊本大学, 国際先端医学研究機構, 客員教授 (30836367)
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| Co-Investigator(Kenkyū-buntansha) |
指田 吾郎 熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Hematopoietic stem cells / Inflammation / Toll-like receptor / Transformation / Regeneration / Histone methylation / Hematopoietic stem cell / MYD88 / TLR / SETD2 / Epigenetics / Stress |
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| Outline of Research at the Start |
The functionality of hematopoietic stem cell (HSC) compartment hinges on the limited reversible balance between quiescence and activation. The identity of cell-intrinsic mechanisms required to terminate activation and re-enter dormancy, and the signaling pathways that mediate this transition, remain unresolved key questions. Based on our data, we propose that“A crosstalk between inflammation and epigenetics controls HSC fitness”through nucleocytoplasmic shuttling of an E3 ubiquitin ligase Speckle-type POZ protein (SPOP) functioning in MYD88 or SETD2 degradation.
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| Outline of Final Research Achievements |
The functionality of hematopoietic stem cell (HSC) compartment hinges on the limited reversible balance between quiescence and activation. The identity of cell-intrinsic mechanisms required to terminate activation and re-enter dormancy, and the signaling pathways that mediate this transition, remain unresolved key questions. Based on our data, we have proposed that A crosstalk between inflammation and epigenetics controls HSC fitness through nucleocytoplasmic shuttling of an E3 ubiquitin ligase Speckle-type POZ protein (SPOP) functioning in MYD88 or SETD2 degradation. We observed: (1) In steady state, cytoplasmic SPOP drove MYD88 degradation to decrease H3K36me2 and prevent HSC exhaustion; (2) In response to inflammation, SPOP translocated into the nucleus and subsequently degraded SETD2 to promote expansion of HSC.
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| Academic Significance and Societal Importance of the Research Achievements |
Our study has provided a deeper understanding of HSC homeostasis via the crosstalk between inflammation and epigenetic regulations. It should be able provide new therapeutic strategy for preventing HSCs from exhaustion by inactivation of MYD88-dependent inflammatory activation in the future.
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