| Project/Area Number |
20K06884
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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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| Review Section |
Basic Section 46010:Neuroscience-general-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Guy Adam Tsuda 京都大学, 生命科学研究科, 准教授 (30634779)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Lipid biology / Developmental biology / Neuroscience / Molecular biology / Cell biology / Neurochemistry / Spinal cord / Lysophospholipid / Cell Biology / Lipid Biology / Molecular Biology |
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| Outline of Research at the Start |
I previously found that the lipid Lysophosphatidylglucoside (LysoPtdGlc) is a novel axon guidance cue acting at GPR55, that sorts primary sensory afferents by modality to control axon tract formation in the developing spinal cord. However many aspects of the LsyoPtdGlc/GPR55 signalling mechanism and its biological significance in other systems, is unknown. In this research, I aim to elucidate the mechanism of LysoPtdGlc generation from its parent membrane lipid phosphatidylglucoside by phospholipase A2, and reveal how this signalling axis is involved in nervous system beyond the spinal cord.
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| Outline of Final Research Achievements |
I previously found that lysophosphatidylglucoside (LysoPtdGlc) is a lipid axon guidance cue required for the development of nociceptive axon circuits in spinal cord. In this project, I have discovered that radial glial LysoPtdGlc can exist in two isomeric forms, R-LysoPtdGlc and S-LysoPtdGlc. I found that whilst both R- and S-forms activate the orphan receptor GPR55, they signal via different downstream intracellular cascades: R-LysoPtdGlc induces Galpha13 activation, whilst S-LysoPtdGlc activates GalphaS. In an assay of axon chemotropism, I discovered that the two isomers, although they both activate GPR55, induce cellular chemotropic response of opposite polarity: R-form induces chemorepulsion, S-form induces chemoattraction, strongly suggesting a mechanism of functional selectivity or ligand bias at GPR55. Neither form induces a response in neurons genetically lacking GPR55. I have also obtained preliminary data for R- and S-forms in an in vivo model of mouse neuropathic pain.
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| Academic Significance and Societal Importance of the Research Achievements |
I determined that the axon guidance cue LysoPtdGlc can exist as one of two biologically active isomers: R-LysoPtdGlc and S-LysoPtdGlc. I found that downstream of GPR55, R-LysoPtdGlc activates Galpha13 whilst S-LysoPtdGlc activates GalphaS, strongly suggesting that they are biased ligands of GPR55.
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