Establishing a framework for EGFR attenuation through structure-guided targeting of GGA2
| Project/Area Number |
19K21288
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| Project/Area Number (Other) |
18H06183 (2018)
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund (2019)
Single-year Grants (2018) |
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| Review Section |
0901:Oncology and related fields
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
Bokhove Marcel 福島県立医科大学, 医学部, 博士研究員 (30825526)
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| Project Period (FY) |
2019-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | GGA2 / EGFR / Crystallography / Signal-disruption / Protein complex / FLIM / Confocal microscopy / Adaptor protein complex / Protein Complex |
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| Outline of Research at the Start |
GGA2 is a molecule that transports proteins in the cell. One such protein is EGFR, which regulates cell growth. Active and inactive EGFR is balanced by recycling or breakdown and reuse of its building blocks. Disruption of this balance can cause cells to develop into dangerous cancers.
Overactivity of GGA2 is linked to certain cancers, but its disruption can slow tumour growth. In this project we want study the GGA2/EGFR complex structure. This complex can be used to design small molecules (medicines) that mimic EGFR, bind and disrupt GGA2, thereby slowing down cancers in a novel way.
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| Outline of Final Research Achievements |
The goal is to obtain a GGA2-EGFR-jxt complex to design anticancer drugs. I made many constructs to study the interaction for structural studies. I could not corroborate previous experiments. Therefore,I made fluorescent resonance energy transfer pairs for fluorescence microscopy. Many constructs were screened for interactions, but I was unable to obtain a complex.
A GGA2 monoclonal would be an invaluable tool in detection of GGA2 in tumours of patients with EGFR-dependent cancers. I produced GGA2hinge, which was used to generate monoclonal antibodies. I purified the antibody from culture medium, which is now used to analyse patient materials.
I shifted my project to the mu adaptor protein (APmu) involved in EGFR recycling. Many (un)fused constructs were made for expression in bacterial cells. I was unable to obtain protein for structure studies. Expression in mammalian cells also failed, suggesting that APmu is toxic. More experiments are needed, but that is outside the time limit.
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| Academic Significance and Societal Importance of the Research Achievements |
I could not achieve my goal. I wanted to develop anticancer drugs to interfere with GGA2-EGFR by structure-based design. No suitable protein complex was made.
I could make protein for GGA2 antibody generation and purification. This antibody could be a tool towards personalised cancer treatment.
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Report
(3 results)
Research Products
(1 results)
