Mnk1对肺动脉高压肺血管重构的影响及其分子机制研究

Pulmonary arterial remodeling is the fundamental pathological feature of pulmonary arterial hypertension (PAH). However, the molecular mechanism with respect to the remodeling of the pulmonary vascular bed remains elusive. The cardinal characteristic of arterial remodeling is unexplained proliferation and relative resistance to apoptosis of the pulmonary smooth muscle cells, which is analogous to carcinogenesis and led to the cancer-like concept. The enhanced smooth muscle cell proliferation accompanied with reduced apoptosis led to the accumulation of smooth muscle cells in the pulmonary arterial wall, the so called muscularization, which ultimately result in stenosis or even occlusion of the pulmonary artery. Mnk1, based on its regulatory role in cell proliferation and apoptosis, has emerged as an important regulator in carcinogenesis. However, the role of Mnk1 in PAH has not been reported. Herein, this project was aimed at dissecting the role of Mnk1 in PAH. In our preliminary experiments, we found that Mnk1 knockout greatly protects the mice from hypoxia and SU5416 induced PAH. In the following study, we are going to use gain- and loss-of-function approaches in animal, cellular, and molecular experiments to dissect the underlying regulatory mechanism of Mnk1 in PAH. Finally, we are going to apply the Mnk1 inhibitor in two models of rat PAH to test the efficacy of Mnk1 inhibition in treating PAH. Thus, our study will provide theoretical bases of anti-proliferative and pro-apoptotic strategy and Mnk1 as a new therapeutic target in treating PAH.

肺血管重构是肺动脉高压不可逆发展的重要病理基础，但其发生的分子机制尚未完全阐明，因而目前尚缺乏针对肺动脉重构的治疗药物。肺动脉重构的主要特点：肺动脉细胞尤其是中层平滑肌细胞，发生类似于肿瘤的过度增殖以及凋亡抑制，大量增殖的血管平滑肌细胞促成了血管壁不可逆的增厚和肌化。Mnk1是调控肿瘤细胞增殖及凋亡的重要因子，但是其在肺动脉高压中的作用尚不清楚。本项目前期研究发现，Mnk1基因敲除可以显著抑制小鼠肺动脉高压的发展。基于该发现，本项目拟从Mnk1功能增强和功能缺失两方面，在动物水平、细胞水平和分子水平充分解析Mnk1对于肺动脉平滑肌细胞增殖及凋亡的调控作用及分子机制。最后，本项目还将探索Mnk1抑制剂对于大鼠肺动脉高压的治疗作用，从抑制肺动脉细胞增殖、及促肺动脉细胞凋亡的角度来探索肺动脉高压的治疗策略，探讨将Mnk1作为肺动脉高压的治疗靶点的临床前证据和理论基础。

肺血管重构是肺动脉高压不可逆发展的重要病理基础，但其发生的分子机制尚未完全阐明，因而目前尚缺乏针对肺动脉重构的治疗药物。肺动脉重构的主要特点：肺动脉细胞尤其是中层平滑肌细胞，发生类似于肿瘤的过度增殖以及凋亡抑制，大量增殖的血管平滑肌细胞促成了血管壁不可逆的增厚和肌化。Mnk1是调控肿瘤细胞增殖及凋亡的重要因子。在实验设计、操作与数据分析过程中，发现在细胞学基础上进行分子机制无有意义结果。此外，借助此项目资金资助，同时进行心肌肥厚相关研究，发现羧基末端调节蛋白(Carboxyl-terminal modulator protein ,CTMP)及(Pleckstrin homology-like domain family A member 3，PHLDA3)在小鼠心肌肥厚模型中表达下调，增加或使其过表达可通过抑制AKT信号通路减轻肥大刺激的反应，改善病理性心肌肥厚，为治疗病理性心肌肥厚和心力衰竭提供了新思路。