Elucidation of the pathophysiology of steroid hormone biosynthesis in lipoid congenital adrenal hyperplasia by establishing a mouse or cell line model

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09996
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: Ishii Tomohiro 慶應義塾大学, 医学部(信濃町), 准教授 (70265867)
• Research Collaborator: MIZUNO Yusuke ; SATO Takeshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: StAR / 先天性リポイド副腎過形成症 / ステロイドホルモン生合成 / コレステロール

Outline of Final Research Achievements

The present study developed significant progress in the understanding pathophysiology of lipoid congenital adrenal hyperplasia (LCAH). First, the study successfully established steroidogenic cell lines lacking steroidogenic acute regulatory protein (StAR) and tamoxifen-inducible knockout mice lacking StAR as in vitro and in vivo models for LCAH, respectively. Second, the results of the study demonstrated the presence of StAR-independent steroidogenic pathway, the role of cAMP in the pathway, and the impairment of the pathway secondary to the accumulation of cholesterol esters in the cytosol of adrenocortical cells. Third, the study indicates that the impairment of StAR-independent steroidogenic pathway secondary to the accumulation of cholesterol esters is associated with global reduction of expression levels of genes related to steroidogenesis probably due to reduced expression of NR5A1.

Free Research Field

内分泌・代謝

Academic Significance and Societal Importance of the Research Achievements

Steroidogenic acute regulatory protein（StAR）を欠損したステロイドホルモン産生細胞株、タモキシフェン投与でStARを欠損するマウスを作成して、先天性リポイド副腎過形成症（LCAH）の病態モデルを細胞とマウスの双方で確立した研究は国内外で初めてである。コレステロールエステル蓄積により二次的に障害されるStAR非依存性のステロイドホルモン産生経路を保持する手段が開発されれば、LCAH女性患者の卵巣機能を維持する新たな治療法への発展が期待される。