Discovery of aldosterone synthesis mechanisms and drug target via epigenomic regulation

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H06894
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: Hiroshima University
• Principal Investigator: KAZUHIRO KOBUKE 広島大学, 医系科学研究科(医), 寄附講座助教 (80805648)
• Research Collaborator: Itcho Kiyotaka ; Oki Kenji
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: エピゲノム調節 / アルドステロン / 副腎腫瘍 / 二次性高血圧

Outline of Final Research Achievements

This study reports a comprehensive integration analysis of DNA methylation and mRNA expression in APAs. We demonstrated that GPCR or GPCR-related genes had a much higher incidence of CpG island demethylation in APAs, and due to this demethylation, some receptors were in a state that would facilitate gene transcription. Also We showed that the PCP4 promoter was one of the most hypomethylated in APAs and that PCP4 transcription may be associated with demethylation as well as with CEBPA in APAs.
This study provides important information regarding the molecular mechanisms of ectopic or aberrant receptor expression in APAs and identifies therapeutic or diagnostic targets that could be studied further.

Free Research Field

内分泌

Academic Significance and Societal Importance of the Research Achievements

難治性の二次性高血圧および重症の動脈硬化性疾患の原因となりうる原発性アルドステロン症，なかでも重症となりうるアルドステロン産生腺腫について，その特異的なアルドステロンの過剰産生機構については未だ明らかでない部分が多いが，本研究により，DNAのメチル化を介した遺伝子発現調節機構の変化が，アルドステロン産生腺腫において重要な働きを担っていることが明らかとなった.アルドステロン合成制御機構の分子メカニズムについて詳細が明らかになることにより，新規分子標的治療薬や診断法の開発につながり，疾病の克服につながる.