Chronic Treatment of Hematopoietic PGD Synthase Inhibitor Improves Skeletal Muscle Function and Cardiac Function in DMD

• Project/Area Number: 26293051
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: ARITAKE Kosuke 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (70390804)
• Co-Investigator(Kenkyū-buntansha): 永田 奈々恵 筑波大学, 国際統合睡眠医科学研究機構, 研究員 (80390805)
• Co-Investigator(Renkei-kenkyūsha): URADE Yoshihiro 筑波大学, 国際統合睡眠医科学研究機構, 教授 (10201360)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2014: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: プロスタグランジンD2 / プロスタグランジンD合成酵素 / デュシェンヌ型筋ジストロフィー / 生理活性脂質 / 肥満細胞 / プロスタグランジンD合成酵素阻害薬 / 拡張型心筋症 / 酵素 / プロスタグランジン / 筋ジストロフィー / PGD合成酵素 / mdxマウス / 酵素阻害薬

Outline of Final Research Achievements

We found that the hematopoietic PGD synthase (HPGDS) catalyzed PGD2 production, estimated by its urinary metabolite (tetranor-PGDM), was significantly enhanced in mdx mice, a model for DMD. We also found that HPGDS expressed on the accumulated mast cells or macrophages around the damaged muscle cells in mdx mice. Chronic treatment with an inhibitor for hematopoietic PGD synthase efficiently decreased inflammatory cell migration in muscles and grouped-necrosis of skeletal muscle, and improved the decrement of locomotor activities, and also ameliorated the isolated skeletal muscle contraction of mdx. HPGDS inhibitor treated mdx hearts were less fibrotic, reductions in left ventricular mass and ejection fraction and fractional shortening were also observed. These results demonstrate that over production of PGD2 catalyzed by HPGDS accelerate the DMD pathology and the pharmacological inhibition of hematopoietic PGD synthase might provide functional benefit to DMD patients.

Research Products

• [Journal Article] Prostaglandin D2 attenuates bleomycin-induced lung inflammation and pulmonary fibrosis (2016)
  • Author(s): Kida Taiki, Ayabe Shinya, Omori Keisuke, Nakamura Tatsuro, Maehara Toko, Aritake Kosuke, Urade Yoshihiro, Murata Takahisa
  • Journal Title: PLoS One Volume: 11(12) Issue: 12 Pages: e0167729-e0167729
  • DOI: 10.1371/journal.pone.0167729
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemogenetic inhibition of the medial prefrontal cortex reverses the effects of REM sleep loss on sucrose consumption (2016)
  • Author(s): McEown K, Takata Y, Cherasse Y, Nagata N, Aritake K, Lazarus M
  • Journal Title: eLife Volume: 5
  • DOI: 10.7554/elife.20269
  • NAID: 120007135235
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interleukin-1β induces sleep independent of prostaglandin D2 in rats and mice. (2016)
  • Author(s): Zhang BJ, Shao SR, Aritake K, Takeuchi A, Urade Y, Huang ZL, Lazarus M, Qu WM.
  • Journal Title: Neuroscience Volume: 340 Pages: 258-267
  • DOI: 10.1016/j.neuroscience.2016.09.053
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Zinc-containing yeast extract promotes nonrapid eye movement sleep in mice. (2015)
  • Author(s): Cherasse Y, Saito H, Nagata N, Aritake K, Lazarus M, Urade Y.
  • Journal Title: Mol Nutr Food Res. Volume: 74 (11) Issue: 10 Pages: 2087-2093
  • DOI: 10.1002/mnfr.201500082
  • Peer Reviewed
• [Journal Article] PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia. (2015)
  • Author(s): Nakamura T, Maeda S, Horiguchi K, Maehara T, Aritake K, Choi BI, Iwakura Y, Urade Y, Murata T.
  • Journal Title: Nat Commun Volume: 10;6 Issue: 1 Pages: 7514-7514
  • DOI: 10.1038/ncomms8514
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis. (2014)
  • Author(s): Moniot B, Ujjan S, Champagne J, Hirai H, Aritake K, Nagata K, Dubois E, Nidelet S, Nakamura M, Urade Y, Poulat F, Boizet-Bonhoure B.
  • Journal Title: Development Volume: 141（１８） Issue: 18 Pages: 3561-3571
  • DOI: 10.1242/dev.103408
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Lipocalin-type prostaglandin D synthase: a transporter of prostaglandin D2 and scavenger of prostaglandin D2-degraded products. (2016)
  • Author(s): Kosuke Aritake, Shigeru Shimamoto, Yoshihiro Urade.
  • Organizer: Lipid Mediator & PLA2 Program
  • Place of Presentation: サンディエゴ（米国）
  • Year and Date: 2016-05-19
  • Int'l Joint Research
• [Presentation] 肥満細胞由来のPGD2はアナフィラキシーを抑制する (2015)
  • Author(s): 中村達朗、山田涼太、前田真吾、有竹浩介、裏出良博、村田幸久
  • Organizer: 獣医学会
  • Place of Presentation: ベルリン（ドイツ)
  • Year and Date: 2015-09-07
• [Presentation] Inhibition of hematopoietic prostaglandin D synthase improves symptoms of muscular dystrophy in a mouse model of Duchenne muscular dystrophy (2014)
  • Author(s): Tanaka K, Aritake K, Tayama M, Shigeno K, Hayashi Y, Sasaki E, Utsugi T,Sasaoka T, Urade Y
  • Organizer: SFN (北米神経科学会)
  • Place of Presentation: ワシントンDC, アメリカ
  • Year and Date: 2014-11-15
  • Int'l Joint Research
• [Presentation] Novel inhibitor of hematopoietic prostaglandin D synthase improves the muscle disorder in an experimental model of Duchenne muscular dystrophy (2014)
  • Author(s): TANAKA K., ARITAKE K., TAYAMA M., SASAKI E., UTSUGI T., SASAOKA T., URADE Y
  • Organizer: World Muscle Soceiety (国際筋肉学会)
  • Place of Presentation: ベルリン、ドイツ
  • Year and Date: 2014-10-07
  • Int'l Joint Research