Analysis of drug regulation mechanisms of functional pituitary tumors by focusing on circadian rhythm

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17985
• 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: Okayama University
• Principal Investigator: komatsubara motoshi 岡山大学, 大学病院, 医員 (80794338)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: オレキシン / インクレチン / 下垂体 / 褐色細胞腫 / BMP / 概日リズム

Outline of Final Research Achievements

Tumors that overproduce hormones with circadian rhythms are characterized by dysregulation of secretory rhythms and disruption of feedback mechanisms, but the underlying mechanisms are not fully understood. In the present study, we investigated the role of orexin, which is involved in sleep-wake regulation, in regulation of ACTH synthesis, focusing on the relationship with BMP signaling by using the mouse pituitary corticotrope tumor cell line AtT20. It was shown that Orexin A promoted ACTH synthesis by enhancing the expression of CRH receptors as well as suppressing BMP-Smad signaling.
In addition, we investigated the effects of incretins on catecholamine synthesis in rat pheochromocytoma PC12 cells to evaluate the relationship between feeding regulation and autonomic nervous system. The results suggest that GIP is involved in the regulation of catecholamine synthesis in cooperation with steroids and BMP-4 action.

Free Research Field

内分泌学

Academic Significance and Societal Importance of the Research Achievements

ホルモンを過剰産生する機能性腫瘍の治療の第一選択は手術による摘出であるが、多くの症例で術後薬物治療を要する。手術不能例や薬剤治療抵抗例、副作用による使用不能例に対する有効な治療法がなく臨床課題となっている。我々のグループでは各内分泌臓器でのホルモン調節機構について概日リズム、摂食調節などの生体リズムとBMP作用の関連に着目して検討してきた。今回の検討では中枢神経で睡眠覚醒に関与するオレキシンが下垂体ACTH合成促進に働くことを明らかにした。生体リズム、フィードバック機構に着目し、ホルモン調節メカニズムを更に検討することでホルモン過剰産生腫瘍に対する新たな治療戦略を模索していく。