Exploration of the coupling partner and the potential inhibitor of a novel smooth muscle contraction regulator, p63RhoGEF

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21245
• Project/Area Number (Other): 18H06129 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Tokyo University of Science, Yamaguchi
• Principal Investigator: Momotani Ko 山陽小野田市立山口東京理科大学, 薬学部, 教授 (00824848)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: p63RhoGEF / GEFT / RhoA / 平滑筋

Outline of Final Research Achievements

This study aims to explore and identify an association partner of a smooth muscle contraction regulatory protein p63RhoGEF. A newly identified partner will eventually be applied for the screening of the inhibitory compound of p63RhoGEF.
Overexpression of various versions of tagged p63RhoGEF in mammalian cells resulted mostly in success. However, overexpression of p63RhoGEF in yeast cells for a future project of inhibitory compound screening was not achieved within the given time. The crucial role of p63RhoGEF in vascular smooth muscle contraction regulation was successfully confirmed using ex vivo mouse micro-vessels.
During this study, the presence of an unknown regulatory element modifying the most downstream of smooth muscle contraction regulatory pathway, myosin light chain phosphorylation, had been suggested. This unknown element was identified as RSK2 kinase and reported on Science Signaling Journal.

Free Research Field

血管平滑筋生理学

Academic Significance and Societal Importance of the Research Achievements

血管の異常収縮が高血圧を引き起こすことはよく知られています。本研究は、血管収縮に関わる新たな因子の特定し、その因子の阻害剤の特定による高血圧治療薬の開発につなげていくことを目指しました。現在既にいくつかの高血圧治療薬は存在していますが、いずれも副作用の問題があり、高血圧治療薬の選択肢を増やすことによってそれらの副作用回避の可能性を広げることは喫緊の課題です。本研究では、当初予想していた通りの新たな因子の特定には至りませんでしたが、研究途上において示唆された、全く新しい別の因子の特定に成功し、これは既存の高血圧治療薬とは全く異なる新たな高血圧治療薬へ道を開く成果と考えます。