Mechanisms of endothelial specific expression and downstream signaling of SGK1 protein kinase in embryonic vascular development

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20751
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: HARADA Yukihiro 国立研究開発法人国立循環器病研究センター, 研究所, リサーチフェロー (70911402)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 心血管発生 / 内皮細胞 / リン酸化酵素 / SGK1

Outline of Final Research Achievements

For SGK1 upstream signaling pathways, I analyzed conservation among species and histone modifications around the SGK1 gene and validated them in lacZ reporter mice, and identified proximal and distal enhancers with endothelial specific transcriptional activity. I further narrowed down these enhancer regions to a few hundreds bp and identified ETS transcription factor consensus binding elements, which are common to both enhancers, and are essential for their transcriptional activities.
For signaling pathways downstream of SGK1, I performed phosphoproteomic analysis of cultured endothelial cells expressing inactive or constitutively active SGK1. I identified several novel substrate candidates, including factors known to be important for endothelial cell regulation and cardiovascular development.

Free Research Field

発生生物医学

Academic Significance and Societal Importance of the Research Achievements

心血管発生・形態形成を制御するシグナル伝達系の異常は遺伝性血管病や先天性心疾患などの難病の原因となるが、血管内皮におけるSGK1の上流・下流シグナルの研究はほとんど進んでいない。近年、血管内皮におけるSGK1の機能解析は本研究を除くとMEK/ERK・細胞増殖における意義の報告があるのみであり、成人循環器疾患において既に創薬ターゲットとして開発が進むことと対象的である。したがって、本研究により明らかにされたSGK1の血管内皮細胞における上流および下流シグナル伝達経路は国内外を問わず新規性があり、臨床的にも重要な知見をもたらすことが期待される。