DL0805衍生物调控BMPR/ROCK/Smad信号通路抗肺动脉血管平滑肌细胞表型转化作用机制研究

肺动脉高压(PAH)是一种高致死率疾病，其主要是由于肺动脉血管发生结构和功能病变所导致，其中肺动脉血管平滑肌细胞(PASMC)表型转化发挥了重要作用。近些年来研究表明，骨形成蛋白受体(BMPR)可经ROCK依赖或非依赖性途径激活下游Smad通路，在PASMC表型转化过程中可能发挥重要的病理生理作用，但其作用机制目前未被阐明。.DL0805衍生物是本实验室前期筛选得到的以吲唑为母核的全新结构小分子ROCK抑制剂，研究发现其通过抑制ROCK通路、上调BMPR2通路改善野百合碱所致PAH大鼠的肺动脉血管结构和功能。本课题旨在明确BMPR/ROCK/Smad通路在PASMC表型转化过程中的分子机制，并基于该通路确认DL0805衍生物作用靶点。本课题预期将更深层次地认识PAH发生机制、对药物作用靶点进行确证并发现新型抗PAH药物，为PAH的治疗提供新的思路和途径，具有较强的创新性和重要科学意义。

Pulmonary artery hypertension (PAH) is a severe disease with high fatality rate. It is generally caused by the structural and functional pathological changes of pulmonary artery vessels, especially the phenotypic switch of pulmonary artery smooth muscle cells (PASMCs). Recent researches show that BMPRs involve in the phenotypic switch of PASMCs and play various physiological or pathological roles by phosphorylating Smads through ROCK dependent or independent pathway, which has not been fully elucidated. .DL0805 derivatives are new chemical entities discovered in our previous work and exhibit ROCK inhibitory effect. Our studies have found that DL0805 derivatives exerted therapeutic effect on PAH rats induced by monocrotaline. They significantly improve the structure and function of pulmonary arteries through the inhibition of ROCK pathway and the up-regulation of BMPR pathway. Based on above, in the present study, we aim to illuminate the mechanisms of BMPR/ROCK/Smad pathway in PASMCs phenotypic switch and figure out the action targets of DL0805 derivatives on this pathway. This project is expected to have a deeper understanding of PAH, verify drug targets and develop novel anti-PAH drug candidates, which provide new ideas for PAH treatment and is highly innovative.