Identification and characterization of the target proteins of anti-inflammatory lipid mediator

• Project/Area Number: 19K07357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Juntendo University
• Principal Investigator: OKUNO TOSHIAKI 順天堂大学, 大学院医学研究科, 非常勤講師 (60361466)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); 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); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: SLCO2A1 / CEAS / プロスタグランジン / 慢性腸疾患 / 輸送体 / 小腸潰瘍 / ５ーリポキシゲナーゼ / プロポフォール / 麻酔薬 / ロイコトリエンB4 / 抗炎症 / ロイコトリエン / LPS / 脂質

Outline of Research at the Start

リポキシン、レゾルビンやプロテクチンなどの抗炎症性脂質メディエーター(SPM)は、特異的なGタンパク質共役型受容体(GPCR)を介して抗炎症性作用を発揮すると考えられているが、その受容体や作用機序の詳細は未だ不明な点が多い。本研究ではSPMの受容体を明らかにし、シグナル活性化機構の解明や受容体欠損マウスを用いた解析によって、抗炎症作用を発揮する分子機序を明らかにする。

Outline of Final Research Achievements

Chronic intestinal diseases associated with the SLCO2A1 gene (CEAS) are caused by loss-of-function mutations in SLCO2A1, which encodes a prostaglandin (PG) transporter. We found a family member who presented to Juntendo Hospital with chronic non-specific ulcers and identified a novel SLCO2A1 mutation by genetic analysis. The levels of urine PG metabolites in patients with ulcers were much increased. We also showed that the novel SLCO2A1 mutation causes loss of PGE2 transporter function and induces CEAS.

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまで知られていなかった新規のSLCO2A1の遺伝子変異を同定した。さらに、変異型輸送体に輸送機能がないことを実験的に証明した。本研究で確立した変異型SLCO2A1の機能解析法、及び質量分析計を用いた尿中代謝物の測定は、患者さんの負担の少ない方法で病態の解明や治療法の開発につながることが期待される。

Research Products

• [Int'l Joint Research] Department of Pharmacology/Vanderbilt University Medical School(米国)
• [Int'l Joint Research] ハーバード大学/医学部/麻酔科(米国)
• [Int'l Joint Research] Friedrich-Schiller-University Jena/Pharmaceutical/Medicinal Chemistry/Institute of Pharmacy(ドイツ)
• [Int'l Joint Research] Boston Children's Hospital/Anesthesiology/Cardiac Anesthesia Division(米国)
• [Journal Article] A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy. (2021)
  • Author(s): Jimbo K., Okuno T., Ohgaki R., Nishikubo K., Kitamura Y., Sakurai Y., Quan L., Shoji H., Kanai Y., Shimizu T., Yokomizo T.
  • Journal Title: PLoS ONE Volume: 16(2)
  • Peer Reviewed / Open Access
• [Journal Article] Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2. (2021)
  • Author(s): Nakashima F., Suzuki T., Gordon O.N., Golding D., Okuno T., Gimenez-Bastida J.A., Yokomizo T., Schneider C.
  • Journal Title: JACS Au Volume: 1(9) Issue: 9 Pages: 1380-1388
  • DOI: 10.1021/jacsau.1c00177
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eicosanoid profiling in patients with complete form of pachydermoperiostosis carrying SLCO2A1 mutations. (2021)
  • Author(s): Oiwa T., Ishibashi M., Okuno T., Ohba M., Endo Y., Uozumi R., Ghazawi F.M., Yoshida K., Niizeki H., Yokomizo T., Nomura T., Kabashima K.
  • Journal Title: Journal of Dermatology Volume: 48(9) Issue: 9 Pages: 1442-1446
  • DOI: 10.1111/1346-8138.16012
  • Peer Reviewed
• [Journal Article] Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis. (2021)
  • Author(s): Ono Y., Kawakita T., Yoshino O., Sato E., Kano K., Ohba M., Okuno T., Ito M., Koga K., Honda M., Furue A., Hiraoka T., Wada S., Iwasa T., Yokomizo T., Aoki J., Maeda N., Unno N., Osuga Y., Hirata S.
  • Journal Title: Biomedicines Volume: 9(11) Issue: 11 Pages: 1519-1519
  • DOI: 10.3390/biomedicines9111519
  • Peer Reviewed / Open Access
• [Journal Article] Cutaneous Liver X Receptor Activation Prevents the Formation of Imiquimod-Induced Psoriatic Dermatitis. (2021)
  • Author(s): Otsuka M., Egawa G., Dainichi T., Okuno T., Ishida Y., Chow Z., Asahina R., Miyake T., Nomura T., Kitoh A., Yokomizo T., Kabashima K.
  • Journal Title: Journal of Investigative Dermatology Volume: 142(4) Issue: 4 Pages: 1233-1237.e1
  • DOI: 10.1016/j.jid.2021.08.432
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dietary intake of n-3 polyunsaturated fatty acids alters the lipid mediator profile of the kidney but does not attenuate renal insufficiency. (2021)
  • Author(s): Shioda R., Jo-Watanabe A., Lee-Okada H.C., Yasukawa K., Okuno T., Suzuki Y., Yokomizo T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 582 Pages: 49-56
  • DOI: 10.1016/j.bbrc.2021.10.028
  • Peer Reviewed / Open Access
• [Journal Article] Metabolism and biological functions of 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (2021)
  • Author(s): Okuno Toshiaki、Yokomizo Takehiko
  • Journal Title: Prostaglandins & Other Lipid Mediators Volume: 152 Pages: 106502-106502
  • DOI: 10.1016/j.prostaglandins.2020.106502
  • Peer Reviewed
• [Journal Article] Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation. (2020)
  • Author(s): Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Soken Tsuchiya, Toshiaki Okuno, Mai Ohba, Takako Ichiki, Satoshi Iwamoto, Hirotsugu Uzawa, Keiko Kitajima, Chikara Meno, Eri Nakamura, Norihiro Tada, Yoshinori Fukui, Junichi Kikuta, Masaru Ishii, Yukihiko Sugimoto, and Mitsuyoshi Nakao, Takehiko Yokomizo.
  • Journal Title: Cellular & Molecular Immunology Volume: 8 Issue: 6 Pages: 1-13
  • DOI: 10.1038/s41423-020-00559-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy. (2020)
  • Author(s): Jimbo K., Okuno T., Ohgaki R., Nishikubo K., Kitamura Y., Sakurai Y., Quan L., Shoji H., Kanai Y., Shimizu T., Yokomizo T
  • Journal Title: PLoS One Volume: 15(11) Issue: 11 Pages: e0241869-e0241869
  • DOI: 10.1371/journal.pone.0241869
  • Peer Reviewed / Open Access
• [Journal Article] n-3 Fatty Acid and Its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell Dysfunction by Enhancing M?ller BDNF in Diabetic Retinopathy (2020)
  • Author(s): Suzumura Ayana、Kaneko Hiroki、Funahashi Yasuhito、Takayama Kei、Nagaya Masatoshi、Ito Seina、Okuno Toshiaki、Hirakata Toshiaki、Nonobe Norie、Kataoka Keiko、Shimizu Hideyuki、Namba Rina、Yamada Kazuhisa、Ye Fuxiang、Ozawa Yoko、Yokomizo Takehiko、Terasaki Hiroko
  • Journal Title: Diabetes Volume: 69 Issue: 4 Pages: 724-735
  • DOI: 10.2337/db19-0550
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Leukotriene B4 receptor 1 exacerbates inflammation following myocardial infarction. (2020)
  • Author(s): Horii Y, Nakaya M, Ohara H, Nishihara H, Watari K, Nagasaka A, Nakaya T, Sugiura Y, Okuno T, Koga T, Tanaka A, Yokomizo T, Kurose H.
  • Journal Title: FASEB Journal Volume: 印刷中 Issue: 6 Pages: 8749-8763
  • DOI: 10.1096/fj.202000041r
  • Peer Reviewed / Open Access
• [Journal Article] The role of propofol hydroxyl group in 5-lipoxygenase recognition (2020)
  • Author(s): Yuki Koichi、Bu Weiming、Eckenhoff Roderic G.、Yokomizo Takehiko、Okuno Toshiaki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: In press Issue: 4 Pages: 909-914
  • DOI: 10.1016/j.bbrc.2020.03.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Leukotriene A4 hydrolase deficiency protects mice from diet-induced obesity by increasing energy expenditure through neuroendocrine axis. (2020)
  • Author(s): Uzawa H, Kohno D, Koga T, Sasaki T, Fukunaka A, Okuno T, Jo-Watanabe A, Kazuno S, Miyatsuka T, Kitamura T, Fujitani Y, Watada H, Saeki K*, Yokomizo T
  • Journal Title: FASEB J Volume: 34(10) Issue: 10 Pages: 13949-13958
  • DOI: 10.1096/fj.202001148r
  • Peer Reviewed
• [Journal Article] Eicosanoids in Skin Wound Healing. (2020)
  • Author(s): Yasukawa K., Okuno T., Yokomizo T.
  • Journal Title: Int. J. Mol. Sci. Volume: 21(22) Issue: 22 Pages: 8435-8435
  • DOI: 10.3390/ijms21228435
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition. (2020)
  • Author(s): Ishihara E, Nagaoka Y, Okuno T, Kofuji S, Ishigami-Yuasa M, Kagechika H, Kamimura K, Terai S, Yokomizo T, Sugimoto Y, Fujita Y, Suzuki A, Nishina H.
  • Journal Title: Genes Cells. Volume: 25(3) Issue: 3 Pages: 197-214
  • DOI: 10.1111/gtc.12750
  • NAID: 120006873037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. (2019)
  • Author(s): Jo-Watanabe A., Okuno T., Yokomizo T.
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 14 Pages: 3580-3580
  • DOI: 10.3390/ijms20143580
  • Peer Reviewed / Open Access
• [Journal Article] Biosynthesis, biological functions and receptors of leukotriene B4 and 12(S)-hydroxyheptadecatrienoic acid. (2019)
  • Author(s): Okuno T and Yokomizo T.
  • Journal Title: Cutting-Edge Organic Synthesis and Chemical Biology of Bioactive Molecules Volume: 1 Pages: 233-246
  • DOI: 10.1007/978-981-13-6244-6_10
  • ISBN: 9789811362439, 9789811362446
  • Peer Reviewed
• [Journal Article] Volatile anesthetics isoflurane and sevoflurane directly target and attenuate Toll-like receptor 4 system. (2019)
  • Author(s): Okuno T., Koutsogiannaki S., Hou L., Bu W., Ohto U., Eckenhoff R. G., Yokomizo T., Yuki K.
  • Journal Title: FASEB J Volume: 33 Issue: 12 Pages: 14528-14541
  • DOI: 10.1096/fj.201901570r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Alternative Pathway to Leukotriene B4 Enantiomers Involving a 1,8-Diol-Forming Reaction of an Algal Oxylipin. (2019)
  • Author(s): Jagusch H., Werner M., Okuno T., Yokomizo T., Werz O., Pohnert G.
  • Journal Title: Org Lett Volume: 21 Issue: 12 Pages: 4667-4670
  • DOI: 10.1021/acs.orglett.9b01554
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cyclooxygenase inhibition in mice heightens adaptive‐ and innate‐type responses against inhaled protease allergen and IL ‐33 (2019)
  • Author(s): Maruyama Natsuko、Takai Toshiro、Kamijo Seiji、Suchiva Punyada、Ohba Mai、Takeshige Tomohito、Suzuki Mayu、Hara Mutsuko、Matsuno Kei、Harada Sonoko、Harada Norihiro、Nakae Susumu、Sudo Katsuko、Okuno Toshiaki、Yokomizo Takehiko、Ogawa Hideoki、Okumura Ko、Ikeda Shigaku
  • Journal Title: Allergy Volume: 印刷中 Issue: 11 Pages: 2237-2240
  • DOI: 10.1111/all.13831
  • Peer Reviewed / Open Access
• [Journal Article] The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction. (2019)
  • Author(s): Koutsogiannaki S., Hou L., Babazada H., Okuno T., Blazon-Brown N., Soriano S. G., Yokomizo T., Yuki K.
  • Journal Title: FASEB J Volume: 33 Issue: 11 Pages: 12668-12679
  • DOI: 10.1096/fj.201901360r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dietary supplementation of omega-3 fatty acid eicosapentaenoic acid does not ameliorate pruritus in murine models of atopic dermatitis and psoriasis. (2019)
  • Author(s): Lee H. C., Tominaga M., Yasukawa K., Ohba M., Takahashi N., Honda K., Okuno T., Takamori K., Yokomizo T.
  • Journal Title: J Dermatol Sci Volume: 95 Issue: 3 Pages: 130-133
  • DOI: 10.1016/j.jdermsci.2019.07.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Leukotriene B4-BLT1 axis controls neutrophil accumulation via Fcγ receptor-dependent leukotriene B4 production in experimental glomerulonephritis. (2021)
  • Author(s): Shioda R., Jo-Watanabe A., Okuno T., Nakayama M., Yokomizo T., Suzuki. Y.
  • Organizer: American Society of Nephrology(ASN) Kidney Week 2021
  • Int'l Joint Research
• [Presentation] ロイコトリエンB4-BLT1軸はFcγ受容体依存的に腎炎急性期の好中球浸潤を制御する. (2021)
  • Author(s): 塩田遼太郎, 城愛理, 奥野利明, 鈴木祐介, 横溝岳彦.
  • Organizer: 第63回日本脂質生化学会, WEB開催
• [Presentation] LTB4-BLT1軸による糸球体腎炎の病態制御機構の解明と治療への応用. (2021)
  • Author(s): 塩田遼太郎, 城愛理, 奥野利明, 鈴木祐介, 横溝岳彦.
  • Organizer: 第94回日本生化学会, WEB開催
• [Presentation] LTB4-BLT1軸による糸球体腎炎の病態制御機構の解明と治療への応用. (2021)
  • Author(s): 塩田遼太郎, 城愛理, 奥野利明, 中山麻衣子, 横溝岳彦, 鈴木祐介.
  • Organizer: Japan Kidney Council 2021, WEB開催
• [Presentation] ロイコトリエンB4受容体BLT1、BLT2のリガンド認識機構 (2020)
  • Author(s): 奥野利明, 横溝岳彦
  • Organizer: 第93回日本生化学会
• [Presentation] ヒト陣痛における羊水中PGE2蓄積は細胞質型PGE合成酵素依存的である. (2019)
  • Author(s): 奥野利明, 高橋七瀬, 横溝岳彦.
  • Organizer: 第61回日本脂質生化学会
• [Presentation] 代謝におけるロイコトリエンA4水解酵素の役割の解析. (2019)
  • Author(s): 鵜澤博嗣, 古賀友紹, 佐伯和子, 奥野利明, 綿田裕孝, 横溝岳彦.
  • Organizer: 第92回日本生化学会
• [Presentation] Mechanism of prostaglandin E2 accumulation in amniotic fluid during human labor (2019)
  • Author(s): Okuno T, Takahashi N, and Yokomizo T.
  • Organizer: 67th American Society for Mass Spectrometry
  • Int'l Joint Research
• [Presentation] COX-2, cPGES, and SLCO2A1-dependent ammonic PGE2 accumulation during human labor. (2019)
  • Author(s): Okuno T., Takahashi N., Yokomizo T.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] Lysophosphatidic Acid Mediates Acute Inflammatory Pain in Mice Models. (2019)
  • Author(s): Hashimoto Y., Ito N., Saigusa D., Okuno T., Yokomizo T.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] The role of leukotriene A4 hydrolase in metabolism. (2019)
  • Author(s): Uzawa H., Saeki K., Koga T., Okuno T., Miyatsuka T., Watada H., Yokomizo T.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] β2 integrins affect eicosanoid production and breast cancer growth. (2019)
  • Author(s): Koutsogiannaki S., Wang W., Bautista J., Okuno T., Yokomizo T., Yuki K.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] Spatiotemporal regulation of novel DC subsets by LTB4-BLT1 signaling. (2019)
  • Author(s): Koga T., Sasaki F., Saeki K., Okuno T., Nakao M., Yokomizo T.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] Deficiency of BLT1, the high-affinity receptor for LTB4, alleviates allergic conjunctivitis in mice. (2019)
  • Author(s): Hirakata T., Lee C. H., Yasukawa K., Adachi K., Saeki K., Okuno T., Murakami A., Matsuda A., Yokomizo T.
  • Organizer: 60th ICBL, International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] Identification of a novel mutation in SLCO2A1 gene, encoding a prostaglandin transporter. (2019)
  • Author(s): Okuno T., Jimbo K., Ohgaki R., Kanai Y., Shimizu T., Yokomizo T.
  • Organizer: 16th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Int'l Joint Research
• [Presentation] The effects of dietary supplementation of an omega-3 fatty acid eicosapentaenoic acid on pruritus in murine atopic dermatitis and psoriasis models. (2019)
  • Author(s): Yasukawa K., Lee C. H., Tominaga M., Ohba M., Takahashi N., Honda K., Okuno T., Takamori K., Yokomizo T.
  • Organizer: 16th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Int'l Joint Research
• [Presentation] Lysophosphatidic acid mediates formalin-induced inflammatory pain in mice. (2019)
  • Author(s): Hoshino Y., Ito N., Saigusa D., Okuno T., Yokomizo T.
  • Organizer: 49th Annual meeting of the society for Neuroscience
  • Int'l Joint Research
• [Remarks] Publication List
  • URL: http://plaza.umin.ac.jp/j_bio/publication.html
• [Remarks] 発表論文
  • URL: http://plaza.umin.ac.jp/j_bio/publication.html