Discovery of new etiologic molecules for thoracic aortic aneurysm and development of therapeutic strategies (early diagnosis / drug discovery)

• Project/Area Number: 19H03646
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Tohoku University
• Principal Investigator: Shimokawa Hiroaki 東北大学, 医学系研究科, 客員教授 (00235681)
• Co-Investigator(Kenkyū-buntansha): 宮田 敏 帝京大学, 公私立大学の部局等, 教授 (60360343) ; 佐藤 公雄 東北大学, 高度教養教育・学生支援機構, 准教授 (80436120)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 大動脈瘤 / 胸部大動脈瘤

Outline of Research at the Start

胸部大動脈瘤は依然として内科的根治療法のない致死性疾患である。降圧以外に有効性の証明された治療薬は無く、瘤拡大評価と手術適応判断を定期的に繰り返すのが現状である。また、経過観察中に急速に進行して瘤破裂を来す症例も依然として多く、新たな病因蛋白の探索と根本的治療薬開発が求められている。我々は最近、新規病因分子SmgGDSを発見した。このSmgGDSは伸展刺激センサー分子であることを突き止め、SmgGDSを欠損させることにより、世界初の胸部大動脈瘤モデルマウスの開発に成功し論文報告した。本研究では、以上の知見に基づき、全く新しい胸部大動脈瘤の早期診断技術開発とアカデミア創薬スクリーニングを目指す。

Outline of Final Research Achievements

Thoracic aortic aneurysm (TAA) is a fatal disease that causes aortic rupture and sudden death. TAA is still a fatal disease for which there is no medical cure, and there is no proven therapeutic agent other than antihypertensive. In addition, there are still many cases in which aneurysm ruptures rapidly progress during follow-up, and there is a need for the search for new causative proteins and the development of radical therapeutic agents. We conducted a comprehensive analysis using patient-derived aortic tissue and aortic vascular smooth muscle cells, screened for novel etiological proteins, and discovered a novel etiologic molecule, SmgGDS. We found that this SmgGDS is a stretch stimulation sensor and succeeded in developing a TAA model mouse by deleting SmgGDS in vascular smooth muscle cells.

Academic Significance and Societal Importance of the Research Achievements

これまでのTAA治療に関する臨床研究は、いずれも降圧薬の有効性の検証に留まってきた。かつて注目されたMarfan症候群患者におけるアンジオテンシンII受容体阻害薬による上行大動脈瘤拡大の抑制効果については、大規模比較試験により、他の降圧剤に対する優位性は否定された。従って、TAAの病因分子に着目した内科的治療薬は皆無であり、今回発見したSmgGDSに着目した治療薬開発はTAAの新しい治療法開発に繋がり、学術的・社会的意義が高いと考えられる。

Research Products

• [Journal Article] Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A). (2021)
  • Author(s): Kurosawa R, Satoh K, Nakata T, Shindo T, Kikuchi N, Satoh T, Siddique MAH, Omura J, Sunamura S, Nogi M, Takeuchi Y, Miyata S, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 41 Issue: 3 Pages: 1205-1217
  • DOI: 10.1161/atvbaha.120.315731
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension (2020)
  • Author(s): Yaoita N, Satoh K, Tatebe S, Yasuda S, Shimokawa H et al.
  • Journal Title: J Am Heart Assoc . Volume: 9 Issue: 21 Pages: 1-12
  • DOI: 10.1161/jaha.120.015902
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial effects of riociguat on hemodynamic responses to exercise in CTEPH patients after balloon pulmonary angioplasty - A randomized controlled study (2020)
  • Author(s): Aoki T, Tatebe S, Shimokawa H et al.
  • Journal Title: Int J Cardiol Heart Vasc . Volume: 29 Pages: 100579-100579
  • DOI: 10.1016/j.ijcha.2020.100579
  • Peer Reviewed / Open Access
• [Journal Article] Cyclophilin A as a biomarker for the therapeutic effect of balloon angioplasty in chronic thromboembolic pulmonary hypertension. (2020)
  • Author(s): Kozu K, Satoh K, Aoki T, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Shimizu T, Sato H, Konno R, Terui Y, Nochioka K, Kikuchi N, Satoh T, Sugimura K, Miyata S, Shimokawa H.
  • Journal Title: J Cardiol Volume: 75 Issue: 4 Pages: 415-423
  • DOI: 10.1016/j.jjcc.2019.09.010
  • Peer Reviewed / Open Access
• [Journal Article] PIM1 (Provirus Integration Site For Moloney Murine Leukemia Virus) as a Novel Biomarker and Therapeutic Target in Pulmonary Arterial Hypertension (2020)
  • Author(s): Satoh K, Kikuchi N, Shimokawa H.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 3 Pages: 500-502
  • DOI: 10.1161/atvbaha.120.313975
  • Peer Reviewed / Open Access