支链氨基酸代谢障碍介导肌成纤维细胞凋亡抵抗促肺纤维化的作用与机制研究

近年研究表明支链氨基酸（BCAA，包括亮氨酸、异亮氨酸和缬氨酸）可作为信号分子激活mTORC1，参与多种疾病的发生发展。申请人通过生信分析和前期研究观察到肺纤维化（PF）患者与小鼠肺组织发生BCAA代谢障碍和堆积，且单细胞测序结果表明PF患者肺组织中以肌成纤维细胞BCAA代谢障碍为主，但该现象在PF中的作用尚不明确。已知肌成纤维细胞凋亡抵抗是PF不可逆进展的重要机制之一。申请人初步观察到促进BCAA分解可降低PF小鼠肺组织胶原含量，减轻肌成纤维细胞的凋亡抵抗。故我们提出BCAA代谢障碍可能通过mTORC1/p70S6K通路导致促凋亡蛋白BAD失活，诱导肌成纤维细胞的凋亡抵抗参与PF。为此，本项目拟在整体水平观察BCAA堆积对小鼠PF严重程度的影响，并在体外探讨BCAA代谢障碍诱导肌成纤维细胞凋亡抵抗的分子机制，以期揭示BCAA代谢障碍在PF发生发展中的作用和机制，为PF防治提供新思路。

Recent studies have shown that branched-chain amino acids (BCAA), including leucine, isoleucine, and valine, act as signal molecules and participate in the development of many diseases. We have noticed that the BCAA catabolism in lung tissue of pulmonary fibrosis (PF) patients and mice was downregulated through bio-information analysis. Single-cell sequencing results also showed that the defective BCAA catabolism was mainly found in myofibroblasts of the patients with PF. However, the role of BCAA catabolism in PF is still unclear. Apoptosis resistance of myofibroblasts is one of the important mechanisms of the irreversible progression of PF. We have observed that promoting BCAA metabolism could reduce the collagen content of lung tissue in PF mice and attenuate the apoptosis resistance of myofibroblasts. Therefore, we propose that the defective BCAA catabolism induces the inactivation of the BCL-2-associated death promoter (BAD) through the mTORC1/p70S6K pathway, resulting in the apoptosis resistance of myofibroblasts in the development of PF. This project intends to investigate the effects of BCAA accumulation on the development of PF in vivo and to explore the molecular mechanism of BCAA-induced apoptosis resistance of myofibroblast in vitro. This project will reveal the role and mechanism of BCAA metabolism disorder in the development of PF and provide a new target for the prevention and treatment of PF.