PHPT1通过负调控TRPV5/KCa3.1抑制高原低氧性肺高压的作用及分子机制研究

高原低氧性肺高压(HAPH)预后较差，其损伤机制与低氧致肺动脉重构所致外周阻力增大有关。酪氨酸磷酸酶(PHPT1)参与肿瘤迁移等病理过程，我们前期研究发现PHPT1与HAPH可能具有一定相关性，但其作用机制尚不明确。本课题创新性提出PHPT1低表达通过调控TRPV5/KCa3.1诱导肺血管重构是HAPH形成新机制这一假说。为证实这一假说，我们将建立肺动脉特异性PHPT1基因高表达大鼠模型，结合小动物遥测技术，探索PHPT1在HAPH发病中的作用；利用PHPT1 基因敲除/过表达的平滑肌细胞模型，探讨PHPT1是否通过负调控TRPV5作用于KCa3.1介导TGF-β表达影响肺动脉平滑肌细胞重塑；同时深入研究PHPT1通过调节TGF-β下游通路影响肺血管重构的分子机制。本项目通过体内外多个层面探索PHPT1对HAPH的作用及分子机制，将为开展针对性防治HAPH提供新靶点，为临床诊疗开辟新途径。

High altitude hypoxic pulmonary hypertension (HAPH) showed poor prognosis. HAPH has been shown to be associated with increased peripheral resistance caused by pulmonary artery contraction and remodeling. Tyrosine phosphatase (PHPT1) has been indicated to be participated in pathological processes such as tumor migration. We have recently found that PHPT1 has some correlation with HAPH, but the exact mechanism has not been elucidated. We hypothesis that smooth muscle cell remodeling induced by low expression of PHPT1 by regulation of TRPV5 / KCa3.1 acts as the new mechanism underlying for HAPH formation. This experiment will establish a rat model of PHPT1 gene overexpression in pulmonary artery, using small animal telemetry technology to prove the role of PHPT1 in HAPH pathogenesis. Adopting PHPT1 gene knockout / overexpression smooth muscle cell model，we will explore whether PHPT1 affect pulmonary artery smooth muscle cell remodeling through negative regulation of TRPV5 / KCa3.1 expression. At the same time, the relationship between PHPT1 and downstream pathway of TGF-β was explored. All of these data will provide new insight into the prevention and treatment of HAPH.