| Project/Area Number |
21K16271
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
HO Pui・Yu 熊本大学, 国際先端医学研究機構, 特定事業研究員 (40888385)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Discontinued (Fiscal Year 2022)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Hematopoietic stem cell / Trained immunity / Hematopoietic stem cells / Trained innate immunity / Stem cell stress / Bacterial infection |
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| Outline of Research at the Start |
Hematopoietic stem cells (HSCs) maintain lifelong blood cell production, but their dysfunction occurs during ageing, resulting in increased susceptibility to cancers and infections in the elderly. Therefore, it is necessary to find novel strategies to reactivate the aged hematopoietic system to strengthen the host immunity. We propose that by stimulating the aged HSCs with microbial agents, we can train the innate immunity and imprint inheritable immune memory to the HSCs to boost the immune responses during secondary infection.
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| Outline of Annual Research Achievements |
Recent works show that not only adaptive immunity but also innate immunity is capable of memorizing previously-encountered pathogens to develop trained immunity. Accumulating evidences show that HSCs can develop immune memory after microbial infection, although the underlying mechanism still remains unclear. We have previously found that upon gut inflammation, Bacteroides species, one of gram negative bacteria in the gut, infiltrate into body and activate BM haematopoiesis in which hematopoietic progenitor (HPCs) are directed to gut-associated lymph node and generate anti-inflammatory myeloid cells for tissue repair (Hayashi et al., bioRxiv 2021). Thus, we hypothesize that Bacteroides might be able to epigenetically imprint an innate immune memory on HSCs and their derived innate immune cells that exert stronger immunocompetence. To test our hypothesis, we primarily challenged mice with Bacteroides and performed in vivo sepsis model as secondary challenge. Microbial prestimulation can provide cross-protective effect to improve host survival. To elucidate the underlying mechanism, we establish a novel bioinformatic pipeline to integrate single-cell sequencing data, and identified epigenetic priming in anti-inflammatory, innate immunity- and metabolism-related genes at 1-month post-stimulation. The Bacteroides also induced substantial changes in active histone modification in the primed HSCs. Our data suggest that understanding of formation, maintenance and abrogation of innate immune memory in HSCs might help to enforce immune-competent of aged hemato-immune system.
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