First neuronal guidance lipid: Elucidation of biosynthesis and development of lead compounds to support neuronal recovery after injury
| Project/Area Number |
16K08259
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Greimel Peter 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, 専任研究員 (60525541)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | Phosphatidylglucoside / GPCR / Lipids / GPR55 / GPRC / Biosynthesis / lipid-biosynthesis |
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| Outline of Final Research Achievements |
To characterize lysolipid-GPR55 interaction a novel homology model of GPR55 was created. Synthetic access to LysoPtdGlc and selected analogues featuring modifications on the acyl chain and on the phosphate moiety were established. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropism assay in primary sensory neurons. Molecular dynamics simulations of the GPR55 homology model in presence of synthetic lysolipid ligands have been performed and assessed. Combination of the molecular dynamics simulations and biological experiments provided insight into the potential ligand entry port and binding pocket specifics of GPR55. These results highlight the preference for gluco- over inositol- and galacto-configured headgroups. Furthermore, the specific acyl chain length required for GPR55 activation has been determined and is in good agreement with the created homology model of GPR55.
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| Academic Significance and Societal Importance of the Research Achievements |
Detailed characterization of the GPR55 ligand binding pocket is an essential per-requisite for rational design of novel GPR55 specific antagonists, which have a high potential to be applied in neuropathic pain relieve treatments in the future.
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Report
(4 results)
Research Products
(13 results)
