Vascular Inflammation and Atherosclerosis: Pathological Elucidation of the Contribution of Inflammasome Activation to Atherosclerosis

• Project/Area Number: 20K07376
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Ehime University
• Principal Investigator: Kurata Mie 愛媛大学, プロテオサイエンスセンター, 講師 (80423440)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 人体病理 / 自己炎症 / 循環器病理 / 自然炎症 / 動脈硬化 / インフラマソーム / 動脈硬化症

Outline of Research at the Start

動脈硬化症やうっ血性心不全は高齢化社会において克服すべき大きな課題である。大規模臨床研究でIL-1βが治療標的と考えられるようになったものの、動脈硬化症の病態形成にNLRP3インフラマソームがどのように関与しているのかは明らかではない。インフラマソームが恒常的に活性化しているモデルマウスを作成し健常マウスと病理組織を比較することで動脈硬化症におけるインフラマソームの寄与を明らかにする。NLRP3インフラマソームの寄与が大きいことが明らかとなれば、NLRP3インフラマソームのみを標的とした分子標的治療が有効となり、副作用がない創薬につながる。

Outline of Final Research Achievements

Elucidation of the contribution of the NLRP3 inflammasome to arteriosclerosis using a model mouse created by our laboratory that has an existing genetic mutation inserted into Muckle-Wells syndrome, one of the diseases in which the inflammasome is constantly activated. The goal was to Stimulation of splenocytes with LPS resulted in higher IL-1β release compared to wild-type mice. I confirmed that there is These mice were used to obtain phenotypic transitions, blood, and histological samples over a long period of time from the fetal period to 12 months of age. We found that hemodynamics and cardiac morphology changed dramatically in the long-term course.

Academic Significance and Societal Importance of the Research Achievements

心血管疾患、特に動脈硬化症やうっ血性心不全は高齢化社会において克服すべき大きな課題である。これらの疾患の病態には慢性炎症が関与している。炎症抑制、特にIL-1βを抑制することで心血管イベントの二次予防になることが大規模臨床研究で統計学的に明らかになり、IL-1βが治療標的と考えられるようになった。しかしながらIL-1βは多様な免疫応答の要であり阻害による免疫抑制はリンパ増殖性疾患などの原因となりうる。NLRP3インフラマソームの動脈硬化症への寄与が明らかとなれば、NLRP3インフラマソームのみを標的とした分子標的治療が可能となり、副作用のないプレシジョンメディスンが実現する。

Research Products

• [Journal Article] Hypoxic Culture Maintains Cell Growth of the Primary Human Valve Interstitial Cells with Stemness (2021)
  • Author(s): Kanno Kaho、Sakaue Tomohisa、Hamaguchi Mika、Namiguchi Kenji、Nanba Daisuke、Aono Jun、Kurata Mie、Masumoto Junya、Higashiyama Shigeki、Izutani Hironori
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 19 Pages: 10534-10534
  • DOI: 10.3390/ijms221910534
  • Peer Reviewed / Open Access
• [Journal Article] Molecular biology of autoinflammatory diseases (2021)
  • Author(s): Masumoto Junya、Zhou Wei、Morikawa Shinnosuke、Hosokawa Sho、Taguchi Haruka、Yamamoto Toshihiro、Kurata Mie、Kaneko Naoe
  • Journal Title: Inflammation and Regeneration Volume: 41 Issue: 1
  • DOI: 10.1186/s41232-021-00181-8
  • Peer Reviewed
• [Journal Article] Active aneurysm thrombosis after Kawasaki disease in an adult: Insight into anticoagulation therapy (2021)
  • Author(s): Akazawa Yusuke、Inaba Shinji、Sakaue Tomohisa、Kurata Mie、Aono Jun、Yasugi Takumi、Moritani Tomozo、Nishiyama Hikaru、Higaki Takashi、Eguchi Mariko、Yamaguchi Osamu
  • Journal Title: Journal of Cardiology Cases Volume: 23 Issue: 5 Pages: 206-209
  • DOI: 10.1016/j.jccase.2020.11.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathological Evidence of Native Aortic Valve Injury After Impella Support (2021)
  • Author(s): Higashi Haruhiko、Nishimura Takashi、Aono Jun、Sakaue Tomohisa、Kurata Mie、Izutani Hironori、Yamaguchi Osamu
  • Journal Title: Circulation: Heart Failure Volume: 14 Issue: 2
  • DOI: 10.1161/circheartfailure.120.007571
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A single-chain antibody generation system yielding CAR-T cells with superior antitumor function (2021)
  • Author(s): Ochi Toshiki、Maruta Masaki、Tanimoto Kazushi、Kondo Fumitake、Yamamoto Toshihiro、Kurata Mie、Fujiwara Hiroshi、Masumoto Junya、Takenaka Katsuto、Yasukawa Masaki
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 273-273
  • DOI: 10.1038/s42003-021-01791-1
  • Peer Reviewed / Open Access
• [Journal Article] KN3014, a piperidine-containing small compound, inhibits auto-secretion of IL-1β from PBMCs in a patient with Muckle?Wells syndrome (2020)
  • Author(s): Kaneko Naoe、Kurata Mie、Yamamoto Toshihiro、Shigemura Tomonari、Agematsu Kazunaga、Yamazaki Takashi、Takeda Hiroyuki、Sawasaki Tatsuya、Koga Tomohiro、Kawakami Atsushi、Yachie Akihiro、Migita Kiyoshi、Yoshiura Koh-ichiro、Urano Takeshi、Masumoto Junya
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 13562-13562
  • DOI: 10.1038/s41598-020-70513-0
  • Peer Reviewed / Open Access
• [Journal Article] Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review (2020)
  • Author(s): Yoshimatsu Takaharu、Nagai Kozo、Miyawaki Reiji、Moritani Kyoko、Ohkubo Kazuhiro、Kuwabara Jun、Tatsuta Kyosuke、Kurata Mie、Fukushima Mana、Kitazawa Riko、Hamada Junpei、Ochi Fumihiro、Eguchi-Ishimae Minenori、Tauchi Hisamichi、Eguchi Mariko
  • Journal Title: Case Reports in Oncology Volume: 13 Issue: 1 Pages: 358-364
  • DOI: 10.1159/000506044
  • Peer Reviewed
• [Journal Article] Valve Interstitial Cell-Specific Cyclooxygenase-1 Associated With Calcification of Aortic Valves. (2019)
  • Author(s): Sakaue T, Hamaguchi M, Aono J, Nakashiro KI, Shikata F, Kawakami N, Oshima Y, Kurata M,?Nanba D, Masumoto J, Yamaguchi O, Higashiyama S, Izutani H.
  • Journal Title: Ann Thorac Surg Volume: S0003-4975 Issue: 1 Pages: 31717-5
  • DOI: 10.1016/j.athoracsur.2019.09.085
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 病理組織像から考える粥状動脈硬化巣内新生血管の意義 (2020)
  • Author(s): 倉田美恵
  • Organizer: 第６回 血管生物医学会 若手研究会