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Pathologic hematopoietic stem cell determines co-morbid symptoms in autism

Research Project

Project/Area Number 19K16529
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionInstitute of Physical and Chemical Research

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)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
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)
Keywordsautism / 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
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.

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.

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.

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (4 results)

All 2023 2022 2019

All Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (1 results) (of which Invited: 1 results)

  • [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 Chia-Wen、Ellegood Jacob、Tamada Kota、Miura Ikuo、Konda Mikiko、Takeshita Kozue、Atarashi Koji、Lerch Jason P.、Wakana Shigeharu、McHugh Thomas J.、Takumi Toru
    • Journal Title

      Molecular Psychiatry

      Volume: in press Issue: 5 Pages: 1932-1945

    • DOI

      10.1038/s41380-023-01999-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Mol Psychiatr

      Volume: in press Issue: 8 Pages: 3343-3354

    • DOI

      10.1038/s41380-022-01566-y

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Altered Microbiota Composition Reflects Enhanced Communication in 15q11-13 CNV Mice2019

    • Author(s)
      Dian Eurike Septyaningtrias, Chia-Wen Lin, Rika Ouchida , Nobuhiro Nakai, Wataru Suda, Masahira Hattori, Hidetoshi Morita, Kenya Honda, Kota Tamada, Toru Takumi
    • Journal Title

      Neuroscience research

      Volume: 19 Pages: 30671-6

    • DOI

      10.1016/j.neures.2019.12.010

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] A prenatal epigenetic fluctuation underlies systemic immune dysregulation in autism2023

    • Author(s)
      Chia-Wen Lin
    • Organizer
      The Physiological Society of Japan
    • Related Report
      2022 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2024-01-30  

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