Three-dimensional pathophysiological analysis of pulmonary hypertension using tissue-clearing method and mutiphoton microscopy

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17667
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: The University of Tokyo
• Principal Investigator: Takayuki Fujiwara 東京大学, 医学部附属病院, 特任助教 (40836441)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肺高血圧症 / 血管新生 / 組織透明化技術 / 多光子顕微鏡

Outline of Final Research Achievements

We developed a three-dimensional (3D) visualization system, and revealed that a previously uncharacterized but marked angiogenic response in hypoxia-induced (Hx) and Alk1+/－ PH mice models, which was canceled by the administration of VEGFR inhibitor SU5416. Angiogenesis was accompanied by the upregulation of X expression in pulmonary endothelial cells. Pulmonary endothelial-specific X-deficient mice lacked an angiogenic response and developed severe Hx-PH, while the activation of X increased angiogenesis and attenuated Hx-PH. Our results suggest that pulmonary endothelial PGC-1α activation plays a crucial role in preventing PH deterioration and is a potential therapeutic target for PH.

Free Research Field

循環器内科分野

Academic Significance and Societal Importance of the Research Achievements

新規の手法の確立を行い、その応用により、過去には報告しえなかった動物組織の三次元的解析を実践することができた。また難治疾患である肺高血圧症において、新規の治療ターゲットとして期待の持てる因子の探索を行うことができ、新規三次元解析手法が単なる生物現象の観察のみにとどまらず、新規病態解明およびそれを応用した新規治療開発に有用であることを示すことができ、この手法を用いて、他の疾患においても病態解明・治療法開発を推し進められる可能性について示すことが可能であった。