Lymphatic abnormalities in RAS related disorders

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19436
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学系研究科, 教授 (80332500)
• Co-Investigator(Kenkyū-buntansha): 新堀 哲也 東北大学, 医学系研究科, 准教授 (40436134) ; 阿部 太紀 東北大学, 医学系研究科, 助教 (40810594)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: リンパ管発生 / リンパ管内皮 / がん遺伝子

Outline of Final Research Achievements

Noonan syndrome is a congenital disorder that indicates heart disease and intellectual disability. Patients with Noonan syndrome are associated with lymphatic dysplasia, including edema in the fetal period and cervical edema after birth, but the function of RAS oncogene mutations in lymphatic development is not yet clear. In this study, we examined lymphatic development in a mouse model that specifically expresses the RAS oncogene in the lymphatic endothelial cells and in a mouse model with Noonan syndrome. Lymphatic enlargement and dilation were observed due to the expression of RAS gene mutations in the fetal period, but no abnormalities in the vascular system were identified, suggesting lymphatic specificity. These results suggest that activation of the RAS oncogene causes abnormalities in lymphatic vessel development during the fetal period, and the results were published as a paper.

Free Research Field

分子遺伝学

Academic Significance and Societal Importance of the Research Achievements

最近somatic RASopathiesとしてリンパ管腫症などの組織においてもRASの変異が同定されてきた。本研究ではリンパ管腫症の原因であるNRAS変異をリンパ管内皮細胞特異的に発現させたマウスと、ヌーナン症候群モデルマウスにおいて検討を行い、どちらも胎児期にリンパ管異形成が起こることを明らかにした。出生後における病態は今後の検討課題であるが、リンパ管発生の新しい分子機構を明らかにすることは、リンパ管疾患の新しい発症機序解明に貢献すると考えられる。最近はヌーナン症候群やリンパ管異常に対してパスウェイ阻害剤を投与する症例報告も海外から出ており今後の治療法検討に役に立つと考えられる。