| Project/Area Number |
23K19350
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0701:Biology at molecular to cellular levels, and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2023-08-31 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2024: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | ubiquitin code / protein aggregates / aging / E3 ligase |
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| Outline of Research at the Start |
Protein misfolding and aggregation result in aging-related diseases. Ubiquitination regulates this process but the mechanism is unknown. We aim to decipher the ubiquitin codes on aggregates using mass spectrometry and nanobodies to identify therapeutic targets for aging and stress-related diseases.
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| Outline of Annual Research Achievements |
Protein misfolding, aggregation, and proteotoxic stresses contribute to cellular damage and disease. Ubiquitination plays a crucial role in maintaining protein homeostasis by removing toxic aggregates through the ubiquitin-proteasomal system and autophagy.
The purpose of this research is to elucidate the role of ubiquitin codes in toxic aggregate accumulation and help identify new therapeutic targets for age-related diseases to promote healthy aging.
We have found a unique ubiquitin code on toxic protein aggregates. We have established the role of a specific E3 ligase in protein aggregation under age-related stresses. We have generated and characterized unique nanobodies against the specific E3 ligase. We found that these nanobodies can modulate the formation and removal of toxic aggregates.
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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 have been able to establish the association between a specific E3 ligase and the accumulation of toxic protein aggregates under stresses. We have also found a unique ubiquitin code on the toxic aggregates. With the use of unique nanobodies we have been able to modulate the formation and removal of protein aggregates in cells.
Due to these significant findings we have been able to establish our hypothesis and we are progressing according to the proposed plan. We are currently establishing the mechanism underlying the E3 ligase-mediated formation of aggregates.
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| Strategy for Future Research Activity |
So far we have been able to establish the association between a specific E3 ligase and the accumulation of toxic protein aggregates under stresses, and we have screened nanobodies to modulate toxic aggregate formation. Next we will elucidate the detailed mechanisms underlying these processes. Furthermore, we plan to use the nanobodies to identify potential targets that may be involved in aging stress-related toxic aggregate formation. With this information we will screen these potential targets in search of proteins that may mitigate the formation of toxic aggregates under stresses.
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