| Project/Area Number |
23K24288
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| Project/Area Number (Other) |
22H03027 (2022-2023)
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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 (2022-2023) |
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| Section | 一般 |
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| Review Section |
Basic Section 52040:Radiological sciences-related
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| Research Institution | Okayama University |
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Principal Investigator |
樋口 隆弘 岡山大学, 医歯薬学域, 教授 (30739850)
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| Project Period (FY) |
2022-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2024)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2025: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2024: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2023: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
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| Keywords | neutrophil / ARDS / CXCR2 / PET imaging / PET / COVID-19 |
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| Outline of Research at the Start |
Massive neutrophil infiltration in the lung alveolus and their surroundings is important for initiation and progression of ARDS. We focus on the CXCR2, expressed on the cell surface of neutrophils, with the goal of developing neutrophil-specific PET imaging that can be applied clinically.
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| Outline of Annual Research Achievements |
The goal of this study is to develop a PET imaging assay that can specifically detect neutrophils of the lung and other organs by targeting the CXCR2, a chemokine receptor specifically expressed on neutrophils.At present, there is no in vivo imaging technique that can specifically visualize local neutrophil infiltration identified via systemic scanning of human body as well as animals. Therefore, we aim to achieve this by using cutting edge PET molecular imaging technology, which can visualize biomarker molecules with high sensitivity.
In order to determine the PET ligands’ affinities,appropriate cell lines, such as HEK cells stably expressing recombinant human CXCR2, were cultivated. Additional cell lines expressing closely related chemokine receptors, such as CXCR1,was also be established to determine selectivity.
The cold references synthesized in WP1 was evaluated in the assay against natural ligand IL-8, e.g.using [125I]IL-8, and compared to the lead compounds to determine binding affinity. Afterwards, precursors of selected ligands with favourable affinity and selectivity were synthesized and radiolabelled in WP3. The radiolabelled tracers were evaluated again in this assay for specificity cross-checking against original antagonists.
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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 designed and synthesized PET tracer candidates targeting CXCR2 and then did in vitro assays to examine the binding affinity and stability of the compounds. To determine the PET ligands’ affinities and to determine selectivity, cell lines were cultivated expressing chemokine receptors, such as CXCR1, was also be established .
The cold references synthesized were evaluated in the assay against natural ligand IL-8 and compared to the lead compounds to determine binding affinity. Afterwards, precursors of selected ligands were synthesized and the radiolabelled tracers were evaluated in the assay for specificity cross-checking against original antagonists.
Since the initial second-year experimental plan has been completed, we believe that the research progress is generally on track.
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| Strategy for Future Research Activity |
In this project, we will develop neutrophil-specific PET imaging of inflammation by 1) targeting CXCR2, a chemokine receptor specifically expressed on neutrophils, 2) using molecular imaging with PET imaging technology that enables highly sensitive molecular detection, 3) designing an 18F-labeled small molecule tracer formulation suitable for clinical application, through evaluation in synthetic, cellular, and animal experiments.
We did in vitro assays and stablished and optimized radiolabelling methods of the PET tracers in the initial second-year. Next step, ex vivo analysis and biodistribution will be done: in vivo evaluation of at least one candidate tracer in a healthy rodent. Finally, we’ll do the longitudinal PET imaging using the rodent animal models of this disease.
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