探討微小核醣核酸調控細胞自噬作用在慢性血栓栓塞性肺動脈高壓所扮演的角色
The Role of MicroRNA Regulation of Autophagy in Chronic Thromboembolic Pulmonary Hypertension
國立臺灣大學醫學系外科 徐紹勛 教授
中央研究院分生所 薛一蘋 特聘研究員
研究團隊：
臺大外科徐紹勛教授，病理部黃彥霖醫師，中研院分子生物研究所薛一蘋特聘研究員，中研院基因轉殖鼠核心實驗室蔡青宴研究技師及長庚大學呼吸治療學系賴盈如教授
- 目前本計畫執行一年又五個月，已成功整合臺大臨床與病理資源、中研院基因轉殖技術及長庚轉譯研究能量，並完成三方共同發表第一篇論文「TGF-β-induced autophagy in pulmonary artery endothelial cells associated with chronic thromboembolic pulmonary hypertension」Journal of Molecular Medicine (2026) 104:57. (SCI, Q1, 41/192, GENETICS & HEREDITY)。並致謝”國立臺灣大學與中央研究院創新性此合作計畫”: 此研究論文以延續之前研究, 慢性血栓栓塞性肺高壓 (CTEPH) 病人肺動脈病灶、珍貴的病人初代肺動脈內皮細胞(PAEC)、低氧誘發肺高壓與過度表達TGF-β 誘發之肺高壓動物模式進行交叉驗證，證實病灶中膠原沉積增加，且自噬標誌 Beclin-1 與 LC3 上升；機制上則建立 TGF-β/Smad3 誘發內皮細胞自噬之關鍵軸線，並提出 LC3可作為疾病進展、血管重塑與治療反應重要指標。
- 臺大胸腔外科徐紹勛教授提供 CTEPH 臨床診療經驗、肺動脈血栓內膜切除術(PEA) 病人組織與臨床問題導向，黃彥霖醫師負責病理判讀、組織染色及人類病灶特徵確認，使基礎研究能緊扣臨床病理。中研院薛一蘋特聘教授及蔡青宴研究技師提供 CRISPR/Cas9 與基因轉殖小鼠平台，支援microRNA過度表達內皮細胞過度表現模式之建立；長庚賴盈如教授負責肺動脈內皮細胞分子機制、TGF-β/Smad3、自噬調控、riociguat 藥物實驗設計與整合分析。各方由臨床樣本、病理驗證、動物模式到細胞機制形成連續研究鏈，提升成果可信度與轉譯價值。
- 本合作之加乘性在於，臺大有效支援CTEPH 病人樣本稀缺與臨床詮釋困難，中研院則補足疾病缺乏可重複性動物模型之瓶頸，長庚進一步將臨床觀察轉化為可驗證之分子機制與治療假說。在計畫執行一年又五個月期間，三方依各自專長明確分工、密切合作並充分討論，成功建立從臨床樣本、病理驗證、動物模式到細胞分子機制之完整研究架構。共同成果不僅釐清 TGF-β/Smad3-LC3 軸在內皮細胞自噬與 CTEPH 血管纖維化中的關鍵角色，也證明 riociguat 可調控 LC3 表現並改善肺血流動力學，為無法接受手術之 CTEPH 病人提供新的藥物作用機轉。此成果充分展現臺大與中研院創新合作計畫之實質研究影響力與後續延伸潛力。目前本團隊第二篇研究論文亦已進入收尾階段，即將整理投稿。感謝臺大與中研院創新性合作計畫提供此跨機構整合機會，使本研究不僅成為臺灣罕見肺血管疾病跨機構合作之示範，也將持續帶動後續國際合作、臨床轉譯與精準治療應用。
- After one year and five months, this project has successfully integrated the clinical and pathological resources of National Taiwan University, the transgenic and genome-editing expertise of Academia Sinica, and the translational research capacity of Chang Gung University. Through this collaborative framework, the team has published its first joint paper, entitled “TGF-β-induced autophagy in pulmonary artery endothelial cells associated with chronic thromboembolic pulmonary hypertension,” in Journal of Molecular Medicine (2026) 104:57. (SCI, Q1, 41/192, GENETICS & HEREDITY)。 The publication acknowledged the support of the National Taiwan University–Academia Sinica Innovative Joint Program. Building upon our previous studies, this work employed cross-validation using pulmonary endarterectomy (PEA) residual specimens from patients with chronic thromboembolic pulmonary hypertension (CTEPH), as well as patient-derived primary pulmonary artery endothelial cells (PAECs), hypoxia-induced pulmonary hypertension models, and TGF-β-overexpression-induced pulmonary hypertension animal models. The study demonstrated increased collagen deposition and upregulation of the autophagy markers Beclin-1 and LC3 in CTEPH lesions. Mechanistically, it identified the TGF-β/Smad3 pathway as a key driver of endothelial autophagy and further proposed LC3 as an important indicator of disease progression, vascular remodeling, and therapeutic response.
- In this collaboration, Professor Hsao-Hsun Hsu from the Department of Thoracic Surgery at National Taiwan University provided CTEPH clinical expertise, pulmonary endarterectomy (PEA)-derived patient tissues, and clinically relevant research questions. Dr. Yen-Lin Huang contributed pathological interpretation, histological staining, and validation of human lesion characteristics, ensuring that the basic research remained closely connected to clinical pathology. At Academia Sinica, Distinguished Research Professor Yi-Ping Hsueh and Research Specialist Ching-Yen Tsai provided the CRISPR/Cas9 and transgenic mouse platforms, supporting the establishment of endothelial cell-specific microRNA overexpression models. At Chang Gung University, Professor Ying-Ju Lai was responsible for PAEC-based molecular studies, investigation of the TGF-β/Smad3-autophagy axis, riociguat drug-intervention experiments, and integrated data analysis. Together, the three institutions established a continuous research chain spanning clinical samples, pathological validation, animal modeling, and cellular mechanisms, thereby strengthening both the reliability and translational value of the findings.
- The major synergistic value of this collaboration lies in the complementary strengths of the three institutions. National Taiwan University effectively addressed the important of CTEPH patient samples and provided essential clinical interpretation; Academia Sinica helped overcome the bottleneck caused by the lack of reproducible disease-relevant animal models; and Chang Gung University translated clinical observations into testable molecular mechanisms and therapeutic hypotheses. During the first one year and five months of the project, the three teams worked closely through clear division of responsibilities, active discussion, and complementary expertise, successfully establishing an integrated research framework from clinical observation to mechanistic validation. The joint outcomes not only clarified the critical role of the TGF-β/Smad3-LC3 axis in endothelial autophagy and CTEPH-associated vascular fibrosis, but also demonstrated that riociguat modulates LC3 expression and improves pulmonary hemodynamics, providing a new mechanistic basis for pharmacological treatment in CTEPH patients who are not eligible for surgery. These achievements highlight the substantial research impact and future potential of the NTU–Academia Sinica Innovative Joint Program. The team’s second manuscript is currently in the final stage of preparation and will soon be submitted. We sincerely appreciate the opportunity provided by this innovative collaboration program, which has enabled this project to serve as a model for cross-institutional research on rare pulmonary vascular diseases in Taiwan and to further promote international collaboration, clinical translation, and precision therapeutic development.