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2016 Fiscal Year Final Research Report

Studies on GRK2 as a potential drug discovery target for the sepsis syndrome

Research Project

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Project/Area Number 26460336
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionUniversity of Toyama

Principal Investigator

Hattori Yuichi  富山大学, 大学院医学薬学研究部(医学), 教授 (50156361)

Project Period (FY) 2014-04-01 – 2017-03-31
KeywordsGRK2 / 敗血症 / 炎症性サイトカイン / 活性酸素 / 敗血症性脳症 / ミクログリア / iNOS
Outline of Final Research Achievements

While GRK2 was originally discovered for its role in the process of desensitization of agonist-activated GPCRs, emerging evidence suggests that GRK2 can participate in the regulation of diverse cellular responses by phosphorylating a large number of non-GPCR substrates and interacting with a plethora of proteins involved in signaling and trafficking. GRK2 inhibitor was found to mitigate acute lung injury in mice with CLP-induced sepsis. Furthermore, we found using cultured mouse microglia that GRK2 was upregulated by LPS challenge and the knockdown of GRK2 gene expression abrogated the LPS-induced increase in the production of ROS and NO. The pharmacological inhibition of GRK2 was shown to downregulate ROS generation and iNOS expression and to prevent the histopathologic changes in brains of mice with CLP-induced sepsis. Thus, GRK2 may serve as a potentially interesting therapeutic target for sepsis syndrome, including sepsis-associated encephalopathy.

Free Research Field

薬理学

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Published: 2018-03-22  

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