Development of a novel therapy targeting the interaction between mechanical stress and immune-inflammatory responses

• Project/Area Number: 18K19583
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Yamaguchi University
• Principal Investigator: YOSHIMURA Koichi 山口大学, 大学院医学系研究科, 准教授(特命) (00322248)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 大動脈瘤 / 大動脈解離 / 力学刺激 / 循環器外科

Outline of Final Research Achievements

Aortic aneurysm and aortic dissection are life-threatening diseases due to aortic rupture. Since therapeutic options are limited, development of novel pharmacotherapy has been needed. In this study, we found that inordinate level of mechanical stress on macrophages accelerated immune-inflammatory responses. Further, isoform-specific inhibition of c-Jun N-ternimal kinase（JNK）reduced inflammatory responses in macrophages and also slowed disease progression, under mechanical stress conditions.

Academic Significance and Societal Importance of the Research Achievements

本研究における発見から、大動脈瘤・大動脈解離の病変部特有の力学刺激と免疫・炎症応答系との連関が制御可能であることと、その制御が新規治療法に繋がる可能性があることが示された。病変部特有の力学刺激と免疫・炎症応答系との連関を標的とすれば、全身の免疫系には影響しない、副作用の少ない治療法が期待できる。広く慢性炎症性疾患に対する新たな作用機序の抗炎症薬の提供にも繋がる。

Research Products

• [Journal Article] 腹部大動脈瘤から考える運動療法の可能性 (2019)
  • Author(s): 吉村耕一
  • Journal Title: 実験医学 Volume: 37 Pages: 1251-1255
• [Journal Article] Abdominal aortic aneurysms (2018)
  • Author(s): Sakalihasan N, Michel JB, Katsargyris A, Kuivaniemi H, Defraigne JO, Nchimi A, Powell JT, Yoshimura K, Hultgren R
  • Journal Title: Nat Rev Dis Primers Volume: 4 Issue: 1 Pages: 1-22
  • DOI: 10.1038/s41572-018-0030-7
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A Mechanistic Link between Mechanical Stress and Inflammation in the Progression of Aortic Diseases (2018)
  • Author(s): Yoshimura K
  • Organizer: 6th IMAD
  • Int'l Joint Research / Invited