Anatomic microniches and their contribution to vascular remodeling in pulmonary hypertension

解剖微生态位及其对肺动脉高压血管重塑的贡献

• 批准号: 10260854
• 负责人: LAVANNYA M. PANDIT
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260854
• 关键词: Affect; Anatomy; Arteries; Binding; Blood Vessels; Blood flow; Cadaver; Calcium; Calcium ion; Caliber; Calmodulin; Candidate Disease Gene; Cell Line; Cell membrane; Cell physiology; Cells; Cellular biology; Characteristics; Confocal Microscopy; Consultations; Contracts; Data; Development; Disease; Distal; Endothelin Receptor; Endothelin-1; Exhibits; Experimental Genetics; Family; Family member; Fibrosis; Five-Year Plans; Functional disorder; Gene Expression; Genes; Genetic; Growth; Health Sciences; Heart Diseases; Heart failure; Heterogeneity; Human; Hypertrophy; Inherited; Institution; Ion Channel; K-Series Research Career Programs; Knockout Mice; Knowledge; Lesion; Ligands; Link; Lobar; Location; Lung; Lung Transplantation; Lung diseases; Maps; Measures; Medial; Medical center; Medicine; Membrane Potentials; Modeling; Modification; Movement; Muscle; Muscle Contraction; Pathologic; Pathway interactions; Patients; Pharmacology; Play; Population; Potassium; Potassium Channel; Pulmonary Fibrosis; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; RNA; Radiolabeled; Radioligand Assay; Receptor Cell; Research; Resistance; Rest; Risk; Role; Sampling; Sarcoplasmic Reticulum; Signal Transduction; Site; Smooth Muscle Myocytes; Structure of parenchyma of lung; Survival Rate; Testing; Texas; Thromboxane Receptor; United States Department of Veterans Affairs; Universities; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vasoconstrictor Agents; Veterans; Work; base; college; constriction; density; design; effective therapy; experimental study; fibrotic lung disease; gene interaction; human tissue; hypertension control; idiopathic pulmonary fibrosis; interest; knock-down; microscopic imaging; mouse model; new therapeutic target; non-smoking; overexpression; potassium ion; preference; pulmonary arterial hypertension; pulmonary vascular cells; pulmonary vascular remodeling; receptor; restoration; right ventricular failure; thrombotic; trafficking; vascular bed; vascular smooth muscle cell proliferation; vasoconstriction

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.

肺动脉高压（pH）是一种知识渊博的疾病，会导致病理学重塑 肺的较小直径血管，导致心力衰竭。该建议将支持 迫切需要的研究以促进我们目前对肺部发展的了解 高血压。从她的职业发展奖的发现，PI（马里兰州Lavannya Pandit）概述 一个五年计划，以调查K2P（两孔域）钾离子家族的机制 归因于血管平滑肌细胞的通道参与针对的血管重塑 肺部较小的直径抗性 - 肺动脉高压的定义病理特征。 这项工作将在Michael E. Debakey退伍军人事务医疗中心（MEDVAMC）进行， 隶属于休斯敦德克萨斯州医学中心的贝勒医学院。重要的协作研究 将在德克萨斯医学中心（德克萨斯大学卫生大学）的邻近机构中进行 科学中心和休斯顿大学。 离子通道和肺血管细胞生物学领域的著名专家将继续其活跃 在拟议研究的五年期间的参与。来自Exped的初步微阵列数据 人pH肺动脉在K2P通道功能障碍中发挥了作用。我们假设K2P离子 通道功能障碍会导致病理生长和特有较小的平滑肌细胞的收缩 直径阻力容器。科学方法利用原发性肺血管平滑肌细胞 来自较大的导管和较小的抗药性肺vissels vissel 使用pH的小鼠模型进行了pH pH的人类肺组织。我们将测试如何 解剖位置确定特定的K2P离子通道对肺血管光滑细胞的影响 生长和收缩力的细胞内途径。该提案考试的第一个目标是解剖学如何 肺血管床内的位置会影响K2P离子通道表达和血管光滑的功能 肌肉。我们将测量K2P通道表达，电流密度和静膜电位 肺血管平滑肌细胞，将K2P离子通道表达的变化归因于 解剖来源。该提案的第二个目标映射了K2P通道与 通过测量细胞内ETR和TXA2运输，内皮素-1（ETR）和血栓氨基支持解员（TXA2）（TXA2） 使用放射性物体测定和共聚焦微观成像。这些结果链接了K2P的解剖位置 光滑肌肉细胞受体配体信号传导的通道（血管收缩器：内皮素-1和homboxanea2） 目前与pH有关。第三个目标是在K2P离子通道中建立功能作用 通过实验遗传和药理学导致pH血管重塑的细胞过程 修改和恢复。在这些翻译人组织研究的结论中，我们将描述 K2P离子通道在pH Vasculopathy发育中的作用。