| Project/Area Number |
23K21442
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| Project/Area Number (Other) |
21H02972 (2021-2023)
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Multi-year Fund (2024)
Single-year Grants (2021-2023) |
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| Section | 一般 |
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| Review Section |
Basic Section 54030:Infectious disease medicine-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Parrish Nicholas 国立研究開発法人理化学研究所, 生命医科学研究センター, 理研白眉研究チームリーダー (40833851)
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| Project Period (FY) |
2021-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2024)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2024: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
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| Keywords | 内在性ウイルス / ヒトヘルペスウイルス6 / ヒトゲノム / 再活性化 / 大規模解析 / HHV-6 / Endogenous virus / Disease association / WGS / ヘルペスウイルス / 内在性ウイルス様エレメント / 抗ウイルス免疫 / テロメア / 潜伏感染 |
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| Outline of Research at the Start |
約1%のヒトゲノムには、ヒトヘルペスウイルス6（HHV-6）に由来する配列（内在性HHV-6）が存在する。以前我々は、内在性HHV-6が過去に組換えを起こして再活性化した痕跡を見出し、また、バイオバンクの解析から特定の疾患群と統計的関連があることを明らかとした。しかし内在性HHV-6がどのような機序を介して疾患リスクとなるのかについては未だ未解明の点が多い。そこで本研究では、内在性HHV-6に対する免疫応答に着目し、実験的に免疫応答を解析することで、内在性HHV-6の疾患リスクの分子機序を調べる。
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| Outline of Annual Research Achievements |
We have made progress in two areas.
First, we expanded our bioinformatic screening for endogenous HHV-6 in a total of 300,000 whole genome sequences using new datasets from UK biobank and All-of-Us. This screening will allow us to reveal the global association of endogenous HHV-6-positive subjects and find new associations between endogenous HHV-6 and disease.
Second, we have developed a method to screen endogenous HHV-6 by PCR. This uses the pooling of subjects’ DNA and allows us to screen endogenous HHV-6 by PCR at middle-throughput. We already screened for endogenous HHV-6 from approximately 3,000 patients with myocardial infarction. We found 17 patients with endogenous HHV-6, with a prevalence of 0.57%. Out of 17 endogenous HHV-6-positive patients, 6 patients were positive for HHV-6A, 10 patients were positive for HHV-6B, and 1 patient was positive for solo-DR form of HHV-6B. We will further investigate if HHV-6 integration contributes to the progression of coronary artery disease.
In FY2023, we will knock out endogenous HHV-6 from iPSCs carrying endogenous HHV-6 to investigate the disease associations. We will differentiate the cells and test if endogenous HHV-6 would change the cellular phenotype. We will summarize the results of bioinformatic analysis obtained up to now and publish as a paper.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We are making progress as expected, because we were able to get access to UK Biobank and All-of-Us Research Program and perform screening of endogenous HHV-6. In UK Biobank, we screened 200,000 whole genome sequencing data and in All-of-Us, we analyzed 100,000 whole genome sequencing data. This revealed the global distribution of endogenous HHV-6-positive people and will enable us to compare disease association between human populations. Although we were not able to perform wet experiments as planned last year, we were able to expand the bioinformatic screening at biobank-scale this year, and I expect we can publish those data as it is in FY2023.
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| Strategy for Future Research Activity |
We plan to perform a disease association study using the 500,000 subjects we analyzed so far in BioBank Japan, UK Biobank, and All-of-Us. We will primarily detect associations in All-of-Us and will replicate in UK Biobank. Based on disease associations we will find, we will follow up in cell culture experiments. In FY2021, we found iPSCs carrying endogenous HHV-6. We will knock out endogenous HHV-6 in those iPSCs by genome editing, then differentiate them to find the mechanism by which eHHV-6 could change cellular phenotype and thereby increase risk of diseases. We will also wrap up the results obtained in FY2022 as a paper; the bioinformatic screening of endogenous HHV-6 in biobanks and global picture of endogenous HHV-6.
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