Are platelet P2Y receptor heteromers a novel drug target for sepsis pathogenesis?

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19015
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: University of Toyama
• Principal Investigator: Suzuki Tokiko 富山大学, 大学院医学薬学研究部(医学), 助教 (10415531)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 敗血症 / シロスタゾール / P2Y受容体

Outline of Final Research Achievements

The development of disseminated intravascular coagulation during the course of sepsis leads to a poor prognosis. Activation and aggregation of platelets are affected by P2Y1 and P2Y12 receptors, respectively. I reported heteromerization between these receptors. It has been suggested that P2Y12 receptor blockers as antiplatelet drugs are also effective in alleviating the symptoms of sepsis. In this study, I analyzed the relationship between P2Y1-P2Y12 receptors in the pathogenesis of sepsis in order to open up new drug discovery for sepsis treatment. In human platelet precursor cells, we have found that these receptors are regulated by stimulation with inflammation and addition of antiplatelet drugs. I also published a paper on inflammatory stimulation-induced signal transduction changes in lung microvascular endothelial cells, which was derived in the course of this research.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

敗血症の患者数は世界で年間約2700万人であり、そのうち約800万人が死亡していると報告されている。特に進行の過程で血小板の活性化を促進することが引き金となって播種性血管内凝固症候群（DIC）が発症し、全身性炎症症状の激化につながることが知られている。本研究により、血小板活性化や凝集能に大きく関係するP2Y1、P2Y12受容体の発現がヒト血小板前駆体由来細胞において炎症刺激や抗血小板薬によって制御されていることが初めて明らかになった。これは、効果的な治療法のないDICに対する創薬の第一歩となり、学術的、社会的意義は大きい。