Wnk1在肺高血压血管重构中的作用及其机制的基础研究

肺高血压（PH，又称肺动脉高压）治疗困难、预后差、危害严重，其研究的主要难点是具体机制不清和关键分子不明。近年来国内外研究多集中在新的靶点和机制上。课题组在前期研究中通过蛋白质组学筛选出Wnk1为候选分子，预实验结果提示其作用于肺动脉平滑肌细胞增殖和迁移，据此提出假说：低氧诱导肺动脉平滑肌细胞Wnk1表达的上调，通过MAPK-ERK5通路激活HIF-1，进而促进其增殖和迁移；抑制Wnk1可作为干预PH的关键点，从而改善肺动脉血管重构，发挥心肺保护作用。本课题拟采用肺动脉平滑肌细胞作为靶细胞进行细胞水平的研究，通过构建Wnk1敲低或过表达的细胞缺氧模型，重点研究其与MAPK-ERK5和HIF-1信号通路之间的关系；在动物水平上，通过应用Wnk1抑制剂和培育肺动脉条件敲除的模式动物，并构建低氧和野百合碱诱导的PH模型，对干预Wnk1的心肺保护作用进行验证，为PH的防治提供新的靶点和研究基础。

The treatment of pulmonary hypertension (PH) is difficult, the prognosis is poor and the harm is serious. The main difficulties in the study of PH are unclear specific mechanisms and unknown key molecules. Recently, increasing number of researches worldwide are focusing on new targets and mechanisms. In our previous study, we screened WNK1 as a candidate molecule by proteomics, which may play a role in proliferation and migration of pulmonary artery smooth muscle cells. Based on preliminary experimental results, the team proposed the hypothesis: Hypoxia induces upregulation of Wnk1 expression in pulmonary artery smooth muscle cells and activates the HIF-1 signaling pathway through the MAPK-ERK5 pathway, which promotes their proliferation and migration; Inhibition of Wnk1 can be used as a novel intervention target for PH by improving vascular remodeling and cardiopulmonary function. In this study, pulmonary artery smooth muscle cells will be used as target cells for cell-level research, and the relationship between WNK1 and MAPK-ERK5/HIF-1 signaling pathways will be studied by building hypoxic cellular models of WNK1 knockdown or overexpression; At the animal level, the cardiopulmonary protective effects of WNK1 intervention will be verified by applying WNK1 inhibitors and cultivating model animals with pulmonary artery conditional knockout, and establishing PH models induced by hypoxia and monoclinine, thus providing a new target and research basis for the prevention and treatment of PH.