Investigation on the roles for sphingolipid signaling in the regulation of macrophage functions
| Project/Area Number |
17K08542
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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 |
General physiology
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| Research Institution | Ishikawa Prefectural Nursing University |
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Principal Investigator |
Takuwa Noriko 石川県立看護大学, 看護学部, 教授 (70150290)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | マクロファージ / 脂質メディエーター / 遺伝子改変動物 / 遺伝子改変マウス / 細胞系譜特異的遺伝子改変マウス / 炎症 / がん血管新生 |
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| Outline of Final Research Achievements |
The sphingolipid mediator, sphingosine-1-phosphate (S1P), which is generated by the action of sphingosine kinases (SphK1/2), acts through cell surface receptors (S1P1-S1P5) to exsert diverse biological activities. We have reported that S1P2 receptor expressed in blood vessels are required for maintenance of vascular barrier function and inhibition of tumor angiogenesis. In this study, we investigated whether and how the sphingolilid signaling system regulates macrophage functions, by employing two disease models. First, deletion of S1P2 markedly ameliolated bleomycin-induced lung fibrosis. We found that S1P2 expressed in macrophages potentiates expression of inflammatory cytokines such as interleukin-13 to aggravate pulmonary inflammation and resustant fibrosis. Second, deletion of SphK2, but not SphK1, markedly aggravated high fat diet-induced atherosclerosis. We found that SphK2 is required for degradation of phagocytosed lipid droplets through autophagy-lysosome system.
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| Academic Significance and Societal Importance of the Research Achievements |
S1Pは５つの受容体サブタイプを介して多彩な生物効果を発揮し、様々な病態への関与も明らかにされつつある。本研究は第一に、マクロファージのS1P2受容体が肺線維症の増悪に関与することを明らかにし、S1P2特異的遮断薬が肺線維症の治療薬の候補となる可能性を提示した。第二に、これまでその機能が十分明らかでなかったS1P産生酵素の一つSphK2が、S1P産生以外の機序で粥状動脈硬化の進行抑制に働いていること、その分子機構として、粥状動脈硬化の主役（泡沫細胞）であるマクロファージにおいて、貪食脂肪滴のオートファジー-リソソーム系による分解・処理機能遂行に、細胞内のSphK2が必要なことを明らかにした。
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Report
(4 results)
Research Products
(30 results)
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[Journal Article] Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages.2018
Author(s)
Zhao J, Okamoto Y, Asano Y, Ishimaru K, Aki S, Yoshioka K, Takuwa N, Wada T, Inagaki Y, Takahashi C, Nishiuchi T, Takuwa Y.
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Journal Title
PLoS One
Volume: 13
Issue: 5
Pages: e0197604-e0197604
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6.2017
Author(s)
Ohkura SI, Usui S, Takashima SI, Takuwa N, Yoshioka K, Okamoto Y, Inagaki Y, Sugimoto N, Kitano T, Takamura M, Wada T, Kaneko S, Takuwa Y.
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Journal Title
PLoS One.
Volume: 12
Issue: 8
Pages: e0182329-e0182329
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Myotubularin-related protein 4 (MTMR4), a phosphoinositide 3'-phosphatase, regulates endolysosome integrity and autophagy flux in human lung alveolar epithelial A549 cells.2017
Author(s)
PQ Hoa, K Yoshioka, SK Azadul, AT Khin, S Islam, S Aki, S Nakamura, N Takuwa, Y Takuwa.
Organizer
第40回日本分子生物学会年会
Related Report
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[Presentation] Myotubularin-related protein 4 (MTMR4), a phosphoinositide 3'-phosphatase, regulates endolysosome integrity and autophagy flux in human lung alveolar epithelial A549 cells.2017
Author(s)
PQ Hoa, K Yoshioka, SK Azadul, AT Khin, S Islam, S Aki, S Nakamura, N Takuwa, Y Takuwa.
Organizer
第 95 回日本生理学会大会
Related Report
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