Anatomic microniches and their contribution to vascular remodeling in pulmonary hypertension

肺动脉高压(PH)是一种知之甚少的疾病，它会导致肺组织的病理性重塑。 肺血管直径较小，导致进行性心力衰竭。这项提议将支持 迫切需要的研究，以促进我们目前对肺源性心脏病发展的有限理解 高血压。从她的职业发展奖发现出发，PI(Lavannya Pandit，MD)概述了 五年计划研究钾离子K2P(两孔结构域)家族的机制 血管平滑肌细胞的通道参与靶向血管重塑 直径较小的阻力-肺血管，这是肺动脉高压的一个明确的病理特征。 这项工作将在Michael E.DeBakey退伍军人事务医疗中心(MEDVAMC)进行，该中心是 隶属于休斯敦德克萨斯医疗中心的贝勒医学院。重要的合作研究 将在德克萨斯医疗中心(德克萨斯大学健康学院)的邻近机构内进行 科学中心和休斯顿大学。)该项目的开发是在咨询指导下进行的 离子通道和肺血管细胞生物学领域的知名专家将继续他们的活动 在拟议研究的五年期间内参与。来自解释的初步微阵列数据 人肺动脉高压与K2P通道功能障碍有关。我们假设K2P离子 通道功能障碍导致较小的平滑肌细胞的病理性生长和收缩 直径阻力容器。科学方法利用原代肺血管平滑肌细胞 来自较大的管道和阻力较小的肺血管的非吸烟身体对照和 移植PH人肺组织，利用PH小鼠模型进行平行研究。我们将测试如何 解剖位置决定特定K2P离子通道对肺血管平滑肌细胞的作用 细胞内生长和收缩的途径。这项提案的第一个目标是检查如何解剖 肺血管床内位置影响血管平滑肌K2P离子通道的表达和功能 肌肉。我们将测量K2P通道的表达，电流密度和静息膜电位 肺血管平滑肌细胞，归因于K2P离子通道表达和功能的变化 解剖学起源。这项建议的第二个目标描绘了K2P频道和 内皮素-1(ETR)和血栓素A2受体(TXA2)在细胞内转运的研究 使用放射配基分析和共聚焦显微镜成像。这些结果与K2P的解剖定位有关。 平滑肌细胞受体配体信号传导通道(血管收缩药：内皮素-1和血栓素A2) 目前与PH有关的人。第三个目标是确定K2P离子通道在 通过实验遗传学和药理学机制研究PH血管重塑的细胞过程 修改和修复。在这些人类组织翻译研究的结论中，我们将描绘出 K2P离子通道在PH血管病变发生发展中的作用

Pulmonary hypertension (PH) is a poorly understood disease that causes pathologic remodeling of the smaller diameter vessels of the lung, leading to progressive heart failure. This proposal will support the critically needed studies to advance our currently limited understanding of the development of pulmonary hypertension. Launching from her career development award findings, the PI (Lavannya Pandit, MD) outlines a five-year plan to investigate the mechanism by which the K2P (two-pore domain) family of potassium ion channels attributed to vascular smooth muscle cells participates in the vascular remodeling targeted to the smaller diameter resistance-vessels of the lung, a defining pathologic characteristic of pulmonary hypertension. This work will be performed at the Michael E. DeBakey Veterans Affairs medical center (MEDVAMC), which is affiliated with Baylor College of Medicine in the Texas Medical Center, Houston. Important collaborative studies will be performed within neighboring institutions at the Texas Medical Center (University of Texas Health Science Center and University of Houston.) The project has been developed with consultative guidance from renowned experts in the field of ion channel and pulmonary vascular cell biology who will continue their active participation over the five-year duration of the proposed studies. Preliminary microarray data from explanted human PH pulmonary arteries implicated a role for K2P channel dysfunction. We hypothesize that the K2P ion channel dysfunction causes pathologic growth and constriction of smooth muscle cells specific to the smaller diameter resistance vessels. The scientific approach utilizes primary pulmonary vascular smooth muscle cells from both larger conduit and smaller resistance pulmonary vessels of both nonsmoking cadaveric controls and explanted PH human lung tissues with parallel studies utilizing a mouse model of PH. We will test how anatomic location determines specific K2P ion channels’ effect on the pulmonary vascular smooth cell intracellular pathways for growth and contractility. The first objective of this proposal examines how anatomic location within the pulmonary vascular bed affects K2P ion channel expression and function in vascular smooth muscles. We will measure K2P channel expression, current density and resting membrane potential in pulmonary vascular smooth muscle cells, attributing changes in K2P ion channel expression and function to anatomic origin. The second objective of this proposal maps the interaction between the K2P channel and endothelin-1(ETR) and thromboxaneA2 receptors (TXA2) by measuring intracellular ETR and TXA2 trafficking using a radioligand assay and confocal microscopic imaging. These results link anatomic location of the K2P channels to smooth muscle cell receptor ligand signaling (vasoconstrictors: endothelin-1 and thromboxaneA2) that are currently implicated in PH. The third objective is to establish a functional role of K2P ion channels in the cellular processes leading to PH vascular remodeling by experimental genetic and pharmacologic modification and restoration. At the conclusion of these translational human tissue studies, we will delineate the role of K2P ion channels in the development of PH vasculopathy.