缺氧性肺动脉高压中Notch通路对钙敏感受体的调节作用研究

Hypoxia-induced pulmonary hypertension (HPH) is a condition that increase mortality in patients.Recent studies show that both activation of Notch signaling and upregulation of CaSR(Ca2+ sensor receptor) contribute to the development of HPH.Our preliminary data show the CaSR expression was attenuated in HPH rats that pretreated with DAPT which inhibited Notch signaling.The goal of this study is to determine whether and how Notch signaling is involved in the initiation and progression of PH.The central hypothesis are that Notch signaling is required for hypoxia induced CaSR activation and upregulation which contribute to the development of HPH .We propose to study the charaction and effects of the interaction between Notch and CaSR.Two Special Aims are proposed in this project:(1)To characterize the potential effect of Notch signaling on CaSR expression and function in PASMC exposed to hypoxia condition.(2)To determine the expression and function of CaSR in the chronic HPH rats injected by Notch signaling inhibitor,and the change of PH phenotype.This study will be used to better characterize both the Notch-CaSR interaction and its functional effect through a variety of planned experiments ,may led to more effective and specific therapy for HPH.

缺氧性肺动脉高压(HPH)病死率高，无有效治疗药物，机制尚未阐明。我们最近报道了HPH大鼠肺动脉平滑肌细胞（PASMC）上的钙敏感受体(CaSR)被激活且表达增加（Circ Res.2012）。新近我们发现：抑制HPH大鼠中Notch通路后CaSR表达下降，而激活Notch通路后PASMC的胞浆内钙内流增加。基于此，我们提出：Notch通路的激活可保持CaSR的敏感性并增加其表达，引发胞浆内钙浓度升高，导致HPH的发生发展。为证实这一假说，本研究将应用分子生物学、胞浆内钙浓度测定等技术，分别在细胞和动物缺氧模型中探索：a、抑制缺氧状态下PASMC上的Notch通路，检测CaSR的表达和功能，并观察细胞增殖和凋亡；b、抑制HPH大鼠Notch通路，急性分离PASMC后检测细胞上的CaSR表达和功能，并评价肺循环血流动力学和肺动脉重塑变化。本课题将从新的视觉探索HPH的分子调控机制和治疗靶点。

缺氧性肺动脉高压(HPH)病死率高，无有效治疗药物，机制尚未阐明。在发现HPH大鼠肺动脉平滑肌细胞（PASMC）上的钙敏感受体(CaSR)被激活且表达增加（Circ Res.2012）的基础上，本课题在体内体外研究中发现：抑制HPH大鼠中Notch通路后PASMC上CaSR表达下降且功能抑制，肺循环血流动力学改善，肺动脉重塑好转；而激活Notch通路后PASMC的CaSR表达上升且功能激活（胞浆内钙内流增加），肺循环血流动力学恶化，肺动脉重塑加剧；因此，我们认为：Notch通路的激活可保持CaSR的敏感性并增加其表达，引发胞浆内钙浓度升高，导致HPH的发生发展。本课题从新的视觉探索了HPH的分子调控机制和治疗靶点。直接成果发表在主流SCI杂志“Hypertension Research"上2篇。