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: 10513303
• 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/10513303
• 关键词: Affect; Anatomy; Arteries; Binding; Blood Vessels; Blood flow; Cadaver; Calcium; Calcium ion; Calmodulin; Candidate Disease Gene; Cell Line; Cell Separation; Cell membrane; Cell physiology; Cells; Cellular biology; Characteristics; Confocal Microscopy; Contracts; Development; Diameter; Disease; Distal; Elasticity; 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; In Situ; 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; Micro Array Data; Microanatomy; Modeling; Modification; Movement; Muscle; Muscle Contraction; Pathologic; Pathway interactions; Patients; Play; Population; Potassium; Potassium Channel; Proliferating; Pulmonary Fibrosis; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; RNA; Radiolabeled; Radioligand Assay; Receptor Cell; Regional Anatomy; Relaxation; 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; candidate identification; college; constriction; density; design; effective therapy; experimental study; fibrotic lung disease; gene interaction; human tissue; idiopathic pulmonary fibrosis; interest; knock-down; microscopic imaging; mouse model; new therapeutic target; non-smoking; overexpression; pharmacologic; 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）是一种引起肺脏病理性重塑的疾病，目前对其了解甚少