MTMR14在肺动脉高压血管重构中的作用及其机制研究

Pulmonary arterial hypertension is one of the most serious diseases that threat human health and life. Pulmonary vascular remodeling is a distinctive feature of pulmonary arterial hypertension, it is also the main obstacle in treating pulmonary arterial hypertension. It has been found that pulmonary vascular remodeling is closely related to the abnormal proliferation and apoptosis, and Ca2+ is a key signaling pathway in the regulation of vascular remodeling. Myotubularin related protein 14(MTMR14) is a novel phosphoinositide phosphatase, has emerged as an important regulator in cell proliferation and apoptosis through the Ca2+ signaling pathway. However, the role of MTMR14 in pulmonary arterial hypertension has not been reported. Herein, our research group found that the pulmonary vascular remodeling was significantly aggravated in MTMR14 conditional knockout mice in our preliminary experiments. 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 MTMR14 in pulmonary arterial hypertension. Moreover, we are going to try the strategy of overexpression of MTMR14 in the treatment for pulmonary arterial hypertension. Thus, our research will provide a new therapeutic target for this life-threatening disease.

肺血管重构是肺动脉高压的病理生理基础，也是肺动脉高压的治疗难点，而肺动脉平滑肌细胞的增殖亢进及凋亡抑制是导致肺血管重构的主要原因之一。细胞内Ca2+失衡是肺动脉平滑肌细胞增殖异常及凋亡失衡的决定性因素，在肺血管重构过程中发挥关键作用。MTMR14是一种新发现的磷酸肌醇类磷酸酶，通过调节Ca2+信号在细胞增殖和凋亡等生命活动中发挥重要作用，但MTMR14是否参与肺动脉高压的发生发展，目前尚无研究报道。本课题前期研究发现MTMR14基因敲除会显著加重小鼠的肺血管重构，加速肺动脉高压的病情进展。基于上述发现，本项目拟从小鼠MTMR14功能增强和功能缺失等多角度，在动物、细胞和分子等多水平，充分解析MTMR14对肺动脉高压的影响及其机制，明确Ca2+是否为MTMR14调控肺动脉高压的关键信号，并探索以MTMR14作为治疗靶点在肺动脉高压中的应用价值，为开发新型肺动脉高压治疗药物提供实验和理论依据。

由于肺动脉高压病因及病理的复杂性，诊断和治疗存在一定的难度，肺动脉高压至今仍是世界医学界的难题之一。MTMR14是一种新发现的磷酸肌醇类磷酸酶，在细胞增殖和凋亡等生命活动中发挥重要作用，但MTMR14是否参与肺动脉高压的发生发展，目前尚无研究报道。本项目组研究发现，MTMR14 在小鼠肺动脉高压模型肺动脉中的表达显著降低。为了进一步探讨MTMR14在肺动脉高压中的作用，我们选用MTMR14基因敲除和转基因小鼠建立肺动脉高压模型。体内实验表明，MTMR14基因敲除会加重低氧联合血管内皮生长因子受体拮抗剂SU5416刺激诱导的肺动脉高压，而MTMR14过表达能够减轻肺动脉高压血管重构。与体内实验结果一致，腺病毒介导的功能获得或功能缺失实验进一步表明，沉默MTMR14会促进缺氧诱导的平滑肌细胞增殖，抑制细胞凋亡，而过表达MTMR14表现出相反的作用。此外，机制方面，我们发现MTMR14通过调控钙调磷酸酶信号通路调节肺动脉高压。我们的研究首次表明，增加平滑肌MTMR14的表达可能是治疗肺动脉高压的一种新方法，为探寻防治肺动脉高压提供了可能的新靶点和新策略。项目资助发表SCI论文4篇。本研究持续进行中培养研究生10名，其中5名已毕业，5名还在学习中。项目投入经费55万元，已支出53.2151万元，各项支出与项目计划相符。剩余经费1.7849万元，剩余经费将用于本项目研究后续支出。