Elucidation of aldosterone synthesis mechanism based on single cell analysis

• Project/Area Number: 19K17964
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Hiroshima University
• Principal Investigator: Itcho Kiyotaka 広島大学, 病院(医), 助教 (00805666)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 原発性アルドステロン症 / 高血圧

Outline of Research at the Start

本研究では，シングルセル解析を基盤に細胞間情報伝達を介したアルドステロン合成制御機構を解明し，原発性アルドステロン症や高血圧に対する新しい診断・治療戦略の基盤を構築することを目的とするため，下記の3つの主要課題に取り組む．
1.シングルセル解析を用いた遺伝子変異の有無による遺伝子発現量の同定とアルドステロン合成に関わる候補接着因子の同定と発現解析．
2.アルドステロン合成に関わる細胞接着因子の機能解析 (In vitro解析)．
3.細胞接着因子調節を調節した動物モデルの表現型解析 (In vivo解析)．

Outline of Final Research Achievements

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. The diagnosis and treatment of PA are extremely important because excess aldosterone secretion not only causes hypertension but is also associated with a high rate of cardiovascular and renal dysfunction. In this study, we aimed to elucidate the mechanism of aldosterone synthesis via cell adhesion factors and intercellular signaling, which have not been focused on so far. We selected candidate factor A by single-cell analysis of aldosterone-producing adenoma (APA). Analysis is currently underway to infer the mechanism of aldosterone synthesis and APA tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

30歳以上の日本人男性の60%，女性の45%以上が高血圧と言われ、また高血圧患者の5-10%程度を原発性アルドステロン症 (PA) が占めることから、PAは極めて頻度の高い疾患である。PAはアルドステロンを過剰分泌することにより、高血圧を来すだけではなく心血管疾患や腎機能障害を高率に合併するため、その診断・治療は極めて重要である。本研究ではこれまで着目されていない機序を介したアルドステロン合成機構に関与する候補因子を選抜し、PAの新しい治療戦略の開発に役立つ可能性がある。

Research Products

• [Journal Article] Hypomethylation associated vitamin D receptor expression in ATP1A1 mutant aldosterone-producing adenoma (2022)
  • Author(s): Nanao Yuta、Oki Kenji、Kobuke Kazuhiro、Itcho Kiyotaka、Baba Ryuta、Kodama Takaya、Otagaki Yu、Okada Akira、Yoshii Yoko、Nagano Gaku、Ohno Haruya、Arihiro Koji、Gomez-Sanchez Celso E.、Hattori Noboru、Yoneda Masayasu
  • Journal Title: Molecular and Cellular Endocrinology Volume: 548 Pages: 111613-111613
  • DOI: 10.1016/j.mce.2022.111613
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation (2021)
  • Author(s): Kobuke Kazuhiro、Oki Kenji、Gomez-Sanchez Celso E.、Gomez-Sanchez Elise P.、Itcho Kiyotaka、Ohno Haruya、Nagano Gaku、Yoshii Yoko、Baba Ryuta、Kodama Takaya、Arihiro Koji、Hattori Noboru、Yoneda Masayasu
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 20 Pages: 10981-10981
  • DOI: 10.3390/ijms222010981
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Update on Genetics of Primary Aldosteronism (2021)
  • Author(s): Itcho Kiyotaka、Oki Kenji、Ohno Haruya、Yoneda Masayasu
  • Journal Title: Biomedicines Volume: 9 Issue: 4 Pages: 409-409
  • DOI: 10.3390/biomedicines9040409
  • Peer Reviewed / Open Access / Int'l Joint Research