cGMP调控TRPM8介导钙内流与肺动脉高压发病和干预机制的研究

NO/cGMP通路负向调节钙信号传导和钙通道活性在肺动脉高压（PAH）治疗中的应用备受关注。但cGMP调控钙通道的分子机制仍有很多重要问题有待研究。申请人近年来一直关注PAH基础及临床研究，以第一和共同通讯作者发表SCI论文6篇，我们近期研究发现：PAH大鼠肺动脉中TRPM8表达和活性显著降低，激活TRPM8后抑制SOCE，但抑制机制不清；磷酸二酯酶5（PDE5）抑制剂通过增加胞内cGMP水平抑制SOCE，上调TRPM8表达和活性，而上调机制待确定。推测cGMP通过调控TRPM8介导SOCE发挥治疗PAH的作用。本项目拟采用分子生物学、电生理学方法进行cGMP和TRPM8抑制SOCE功能分子机制的研究，明确两者在肺血管中对SOCE功能调控的协同作用，探索PDE5抑制剂和TRPM8通道激活剂联合应用于PAH防治中的可能性，将从新的研究视角为PAH发病机制的探讨和靶向治疗药物的开发提供新思路。

Nitric Oxide/cGMP pathway negatively acts on Ca2+ signal regulation and store-operated Ca2+ channels (SOCC) function plays an important role in the treatment of pulmonary arterial hypertension (PAH). However, the molecular mechanism of cGMP regulating SOCC remains to be studied. The applicant has focused on the basic and clinical researches of PAH, and published six papers in SCI as the first and co corresponding author. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) was down-regulated in PASMCs of PAH animal models, and TRPM8-mediated cation entry was reduced in PAH-PASMCs, and activation of TRPM8 caused inhibition of SOCE, however, the molecular mechanism remains largely unknown. 5-type phosphodiesterase (PDE5) inhibitors inhibited the degradation of cGMP, increased the expression and activity of TRPM8, and treated PAH by negatively regulating SOCE, but the regulatory mechanism remains unclear. We hypothesize that cGMP and TRPM8 interact functionally and contribute to the altered SOCE function in PAH. This project uses molecular biology and electrophysiology technology, to confirm the molecular mechanism of cGMP and TRPM8 mediated inhibition of SOCE, to explore the synergistic effect of cGMP and TRPM8 on regulating the function of SOCE in pulmonary vessels. This is important to clarify the better clinical efficacy and safety of PDE5 inhibitors combined with TRPM8 agonists in the treatment of PAH. In order to provide new scientific basis for elucidating the pathogenesis of PAH and develop novel therapeutic approaches.