2020 Fiscal Year Research-status Report
Pathologic hematopoietic stem cell determines co-morbid symptoms in autism
| Project/Area Number |
19K16529
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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, 訪問研究員 (20730253)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | autism / dysbiosis / brain inflammation / Hdac1 |
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| Outline of Annual Research Achievements |
Autistic patients often carry the comorbidity burden of immune dysregulation. However, mechanisms remain elusive. Here, we demonstrate pathologic progenitors, originating in the yolk sac and aorta-gonad-mesonephros, are responsible for the development of hyperactivated microglia and a skewed immune system. Single-cell RNA sequencing identified a common mechanism of Hdac1-mediated transcriptional repression in both YS and AGM progenitors. This dysregulated epigenetic machinery delayed the process of endothelial to hematopoietic transition, therefore disturbing definitive hematopoiesis during embryogenesis. These findings elucidate a shared origin of co-occurring symptoms in the brain and peripheral tissue and suggest the therapeutic potential to target immune-dysregulated ASD subtypes.
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
With the support of Kakenhi, we made detail plans for the experiments. However, due to the pandemic of COVID-19, the experimental schedules were fell behind. Mice colonies were maintained at minimal number during the emergency period. After the end of emergency status, it took extra period to expand the mice colonies to restart the proposed experiments. The collaboration study, 16s rRNA sequencing, was also postponed for around 6 months. On the other hand, it also took longer time than expected to determine the proper dose of Hdac inhibitor treatment to rescue the comorbid symptoms in BTBR mice. Most dosage and treatment schedules during embryonic stages caused abortion. This suggests the critical role of epigenetic regulation in development and increases the difficulties of rescue.
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| Strategy for Future Research Activity |
To make convincing conclusion, we have designed rescuing experiment in mice based on the finding of 10x genomic sc-RNA seq, increased Hdac activity in YS and AGM progenitor cells. However, due to the prominent role of epigenetic regulation during development, it is not easy to manipulate Hdac levels by pharmalogical treatment. We put in lots of efforts to optimize the dosage and tried different types of Hdac inhibitors. Only until recently, a mild dose was found to work in rescuing brain inflammation and restoring the altered immune composition. We are now increasing the number to verify the results.
The experimental part of our research has been done for 90% and now we are summarizing the results for publication. I sincerely appreciate your understanding for the extension of Kakenhi.
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| Causes of Carryover |
The incurring amounts will be used for the rescuing experiment by Hdac inhibitor treatment. To evaluate the rescuing effect on brain inflammation, cytokine expression profiles will be analyzed by qPCR, from RNA extraction. For peripheral immune dysregulation, FACS will be performed to analyze the cell composition in spleen, lymph node and intestine. Consumptions and reagents will be the main expenditure. We also planned to submit the finding of this study within this year and to attend the SfN neuroscience meeting to have more interaction and feedback from other researcher in this field.
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