肺动脉平滑肌细胞增殖是低氧性肺动脉高压（HPH）主要细胞机制。细胞内Ca2+的变化在细胞增殖的形成过程中起重要的作用。我们前期研究结果表明：肺动脉平滑肌细胞中双孔通道（TPCs）在介导NAADP诱发溶酶体内Ca2+信号释放的过程中起决定性的作用。新近研究也发现低氧能够诱导NAADP合成限速酶CD38活性和表达增加。因此，本项目将探讨低氧是否增强肺动脉平滑肌细胞中CD38活性，催化NAADP合成增加，进而与其溶酶体膜受体TPCs结合，促进溶酶体Ca2+释放，增加细胞内钙离子浓度。Ca2+与CaM形成Ca2+ -CaM复合物，上调Cyclin E/D1和CDK 2/4促进肺动脉平滑肌细胞增殖，导致肺血管重塑形成。本研究将从低氧原代培养的肺动脉平滑肌细胞，低氧性肺动脉高压动物模型和COPD肺动脉高压患者三个层面验证我们的假设，并探讨其细胞分子机制，揭示HPH的发病机制，为HPH的防治提供新的靶点

Pulmonary artery smooth muscle cells (PASMCs) proliferation is major cell mechanism of hypoxic pulmonary hypertension.More attention have been put on the changes of intracellular Ca2+ in the process of cell proliferation. Our previous research have shown that the two pore Channel (TPCs) in pulmonary artery smooth muscle cells play a decisive role in mediating the NAADP-induced Ca2+ release in lysosome.Recent studies have also shown that hypoxia can upregulate the expression of CD38, which is NAADP's synthesis rate-limiting enzyme.Therefore,in this project, we will examine that whether hypoxia enhance CD38's activity in pulmonary artery smooth muscle cells, leading the increase of NAADP, which combine with lysosomal membrane receptor - the two pore Channels (TPCs), promoting the Ca2+ release in lysosome. Moreover,we will further investigate whether the combination of Ca2+ and CaM ,Ca2+ -CaM ,composite upregulate the expression of Cyclin E/D1 and CDK 2/4, leading to PASMC proliferation and vascular remodeling. We will test our hypothesis using primary cultured PASMCs , chronic hypoxia animal models and COPD patient with pulmonary hypertension. The results generated from this project may provide new information on the cellular and molecular mechanism of hypoxic pulmonary hypertension, and identify therapeutic targets for the development of novel treatment for the dreadful disease.