Pathologic hematopoietic stem cell determines co-morbid symptoms in autism
| Project/Area Number |
19K16529
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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 48040:Medical biochemistry-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Lin Chiawen 国立研究開発法人理化学研究所, 脳神経科学研究センター, 客員研究員 (20730253)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | autism / epigenetics / immune dysregulation / gut dysbiosis / sc-RNA seq / endogenous retrovirus / genome susceptibility / copy number variation / single-cell RNA seq / EHT / microbiome dysbiosis / HDAC1 / dysbiosis / brain inflammation / Hdac1 / comorbid symptom / inflammation / progenitors / Autism |
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| Outline of Research at the Start |
To analyze the transcriptome of HSCs from immune-dysregulated autistic mice, it aims 1) to identify the determinant for pathologic HSC development and to unravel the mechanism of immune dysregulation in autism. 2) To screen immune dysregulated autism subtypes.
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| Outline of Final Research Achievements |
The research results were published to reveal the mechanism of immune dysregulation on autism etiology. By tracking the origin of immune dysregulation back to embryonic stage in specific cell types, we found an altered HDAC1 activity affects the definitive hematopoiesis in yolk sac and AGM in an autism model strain (BTBR), which therefore affects the development of microglia and hematopoietic stem cells and subsequently leads to brain inflammation and skewed immune cell profiles. We published another paper to show active ERV also manipulate the transcriptional profiles of BTBR during development. The analogy between ERV reactivation and viral infection again echoes the etiology of in the autism models of environmental risk factor, such as MIA- and VPA- induced models of autism. Active ERV also accelerate CNV formation in the genome. This study unravels the idiopathic mechanism of autism but also provde new insights to how the ancient viral infection affects autism susceptibility.
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| Academic Significance and Societal Importance of the Research Achievements |
The mechanism of immune dysregulation discovered by study can provide the basis to develop biomarker to access the change in peripheral immune system for early autism diagnosis and intervention. This will be important for the increased MIA cases owing to COVID infection during the 2-year pandemic.
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Report
(5 results)
Research Products
(4 results)
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[Journal Article] An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development2023
Author(s)
Lin CW, Ellegood J, Tamada K, Miura I, Konda M, Takeshita K, Atarashi K, Lerch JP, Wakana S, McHugh TJ, Takumi T
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Journal Title
Mol Psychiatry
Volume: in press
Issue: 5
Pages: 1932-1945
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A common pathologic mechanism across cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.2022
Author(s)
Lin C-W, Septyaningtrias DE, Chao H-W, Konda M, Atarashi K, Takeshita K, Tamada K, Nomura J, Sassagawa Y, Tanaka K, Nikaido I, Honda K, McHugh TL, Takumi T
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Journal Title
Mol Psychiatr
Volume: in press
Issue: 8
Pages: 3343-3354
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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