Proposal of Molecular Leverage Hypothesis with Molecular Dynamic Calculation

• Project/Area Number: 17K19669
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine and related fields
• Research Institution: Tokai University
• Principal Investigator: GOTO Shinya 東海大学, 医学部, 教授 (50225653)
• Research Collaborator: OKA Hideki ; GOTO Shinichi
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 血小板 / 膜糖蛋白 / 分子動力学 / 高性能コンピューター / 血栓 / 心筋梗塞 / 膜糖蛋白GPIIb/IIIa / 細胞活性化 / インテグリン / 血小板細胞 / GPIIb/IIIa / Talin / 血小板凝集 / 分子 / 細胞 / シミュレーション / コンピューター

Outline of Final Research Achievements

Platelet activated upon various stimulation. Intra-cellular calcium ion slightly increased upon activation. But, in general, change in intra-cellular environment is not huge. The mechanism transmitting small change in intra-cellar domain of various membrane proteins on the substantial structural changes in extra-cellular domain is unknown. We are proposing "molecular leverage hypothesis" to explain the enlargement of small changes to the larger one by high performance super computers.

Academic Significance and Societal Importance of the Research Achievements

血小板細胞は刺激に応じて活性化する。非活性化血小板は凝集し、活性化血小板は凝集する。血小板凝集は血小板膜糖蛋白GPIIb/IIIaの活性化構造変化に依存する。活性化とともに血小板細胞内のカルシウムイオン濃度は上昇する。GPIIb/IIIaの細胞内ドメインにはTalinなどの接着斑蛋白が結合する。細胞内ドメインの構造も細胞活性化により変化すると想定されるが細胞内ドメインは短いので、構造変化は大きくない。この小さな細胞内ドメインの構造変化が、細胞外ドメインの大きな構造変化と血小板細胞の性質変化を惹起するメカニズムは未知である。このメカニズムとして分子レバレッジ仮説を提案し、妥当性を検証する。

Research Products

• [Journal Article] Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. (2019)
  • Author(s): Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, Desai AS, Goto S, Johansson PA, Gause-Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD.
  • Journal Title: Circulation Volume: in press Issue: 22 Pages: 115-124
  • DOI: 10.1161/circulationaha.119.040130
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Letter by Goto and Goto Regarding Article, "Fully Automated Echocardiogram Interpretation in Clinical Practice: Feasibility and Diagnostic Accuracy" (2019)
  • Author(s): Goto S and Goto S
  • Journal Title: Circulation Volume: 139 Issue: 13 Pages: 1646-1647
  • DOI: 10.1161/circulationaha.118.038451
  • Peer Reviewed / Open Access
• [Journal Article] Management and 1-Year Outcomes of Patients With Newly Diagnosed Atrial Fibrillation and Chronic Kidney Disease: Results From the Prospective GARFIELD - AF Registry. (2019)
  • Author(s): Goto S, Angchaisuksiri P, Bassand JP, Camm AJ, Dominguez H, Illingworth L, Gibbs H, Goldhaber SZ, Goto S, Jing ZC, Haas S, Kayani G, Koretsune Y, Lim TW, Oh S, Sawhney JPS, Turpie AGG, van Eickels M, Verheugt FWA, Kakkar AK
  • Journal Title: J Am Heart Assoc. Volume: 8 Issue: 3
  • DOI: 10.1161/jaha.118.010510
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Artificial intelligence to predict needs for urgent revascularization from 12-leads electrocardiography in emergency patients. (2019)
  • Author(s): Goto S, Kimura M, Katsumata Y, Goto S, Kamatani T, Ichihara G, Ko S, Sasaki J, Fukuda K, Sano M1
  • Journal Title: PLoS One. Volume: 14 Issue: 1 Pages: e0210103-e0210103
  • DOI: 10.1371/journal.pone.0210103
  • Peer Reviewed
• [Journal Article] Characteristics and Management of Patients with Venous Thromboembolism: The GARFIELD-VTE Registry. (2019)
  • Author(s): Ageno W, Haas S, Weitz JI, Goldhaber SZ, Turpie AGG, Goto S, Angchaisuksiri P, Nielsen JD, Kayani G, Pieper KS, Schellong S, Bounameaux H, Mantovani LG, Prandoni P, Kakkar AK
  • Journal Title: Thromb Haemostasis Volume: 119 Pages: 319-327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early Risks of Death, Stroke/Systemic Embolism, and Major Bleeding in Patients With Newly Diagnosed Atrial Fibrillation. (2019)
  • Author(s): Bassand JP, Virdone S, Goldhaber SZ, Camm AJ, Fitzmaurice DA, Fox KAA, Goto S, Haas S, Hacke W, Kayani G2, Mantovani LG10, Misselwitz F, Pieper KS2, Turpie AGG, van Eickels M, Verheugt FWA, Kakkar AK
  • Journal Title: Circulation Volume: 139 Issue: 6 Pages: 787-798
  • DOI: 10.1161/circulationaha.118.035012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan ― Insights From GARFIELD-AF ― (2018)
  • Author(s): Koretsune Y, Etoh T, Katsuda Y, Suetsugu T, Kumeda K, Sakuma I, Eshima K, Shibuya M, Ando SI, Yokota N, Goto S, Pieper KS, Allu J, Kakkar AK
  • Journal Title: Circulation Journal Volume: 83 Issue: 1 Pages: 67-74
  • DOI: 10.1253/circj.CJ-18-0655
  • NAID: 130007550428
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-12-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High rate of death in patients with atrial fibrillation -Results from EORP-AF Pilot General Registry. (2018)
  • Author(s): Ayabe K and Goto S
  • Journal Title: Int J Cardiol. Volume: 271 Pages: 109-110
  • Peer Reviewed / Open Access
• [Journal Article] Overview of oral antithrombotic treatment in elderly patients with atrial fibrillation. (2018)
  • Author(s): Kato ET, Goto S, Giugliano RP
  • Journal Title: Ageing Res Rev Volume: 49 Pages: 115-124
  • DOI: 10.1016/j.arr.2018.10.006
• [Journal Article] Edoxaban's Journey: From East Asia to the Globe, Back to East Asia. (2018)
  • Author(s): Goto S and Goto S
  • Journal Title: J Am Coll Cardiol. Volume: 72 Issue: 8 Pages: 854-856
  • DOI: 10.1016/j.jacc.2018.05.067
• [Journal Article] Antithrombotic therapy use and clinical outcomes following thrombo-embolic events in patients with atrial fibrillation: insights from ARISTOTLE. (2018)
  • Author(s): Goto S, Merrill P, Wallentin L, Wojdyla DM, Hanna M, Avezum A, Easton JD, Harjola VP, Huber K, Lewis BS9
  • Journal Title: Eur Heart J Cardiovasc Pharmacother Volume: 4 Issue: 2 Pages: 75-81
  • DOI: 10.1093/ehjcvp/pvy002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Validation of DAPT Score (Dual Antiplatelet Therapy) in East Asian Patients (2018)
  • Author(s): Yabushita H and Goto S
  • Journal Title: Circulation Volume: 137 Issue: 6 Pages: 563-566
  • DOI: 10.1161/circulationaha.117.031785
  • Peer Reviewed
• [Journal Article] Does Computer Simulation Help Facilitate Personalized Precision Medicine for the Use of Warfarin? (2017)
  • Author(s): Goto S and Goto S
  • Journal Title: Circ Cardiovasc Genet Volume: 10 Issue: 6 Pages: 1-3
  • DOI: 10.1161/circgenetics.117.001969
  • Peer Reviewed / Open Access
• [Presentation] Biologically Validated Model of Platelet Adhesion under Blood Flow Conditions (2018)
  • Author(s): Goto S
  • Organizer: The Scientific Committee of the Joint Meeting of ESCHM-ISB-ISCH
  • Int'l Joint Research / Invited
• [Presentation] 血小板と赤血球および血管壁との衝突を考慮した血管壁接着シミュレーション (2018)
  • Author(s): Yamasawa D and Goto S
  • Organizer: 日本内科学会2018
• [Patent(Industrial Property Rights)] 抗血液凝固剤投薬治療における予後イベント予測 (2019)
  • Inventor(s): 後藤信哉、後藤信一
  • Industrial Property Rights Holder: 学校法人東海大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-038948
  • Filing Date: 2019