Aquaporin 1 and pulmonary hypertension

水通道蛋白 1 和肺动脉高压

• 批准号: 10538750
• 负责人: Larissa A. Shimoda
• 金额: $ 70.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538750
• 关键词: AQP1 gene; Apoptosis; Apoptotic; Binding; Binding Sites; Blood Vessels; Blood capillaries; C-terminal; Cell Adhesion; Cell Hypoxia; Cell Nucleus; Cell Proliferation; Cell Survival; Cell physiology; Cells; Complex; Data; Development; Disease; Distal; Endothelial Cells; Endothelium; Epithelial Cells; Failure; Family member; Human; Hypoxia; Knowledge; Laboratories; Lesion; Lung; Mediating; Modeling; Molecular; Muscle; Mutate; Nuclear; Nuclear Translocation; Pathology; Pathway interactions; Patients; Permeability; Phenotype; Predisposition; Prevention; Protein Family; Proteins; Publishing; Pulmonary Hypertension; Pulmonary arterial remodeling; Rattus; Regulation; Reporting; Repression; Resistance; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Tail; Testing; Up-Regulation; Vascular remodeling; Water; base; beta catenin; cell growth; cell motility; cytochrome c; experimental study; glycogen synthase kinase 3 beta; improved; in silico; insight; lung microvascular endothelial cells; migration; mortality; novel; novel therapeutics; prevent; protein function; protein protein interaction; pulmonary arterial hypertension; pulmonary arterial pressure; renal epithelium; response; right ventricular failure; therapeutic target; water channel

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a severely debilitating disease with no cure. Morphometric studies revealed that the development of pulmonary hypertension is associated with robust structural remodeling of the small pulmonary arteries, characterized by thickening of the endothelial and smooth muscle cell layers and formation of occlusive lesions. In addition to increased proliferation and migration of vascular cells, failure of appropriate apoptosis (i.e., apoptotic resistance) contributes to remodeling via lack of cell turnover. Our laboratory identified a new candidate as a regulator of pulmonary arterial smooth muscle cell (PASMC) function: aquaporins (AQPs). AQPs are a family of proteins that form transmembrane channels which facilitate the transport of water into and out of cells. We have evidence that aquaporin 1 (AQP1), the first family member identified, is expressed in PASMCs and pulmonary microvascular endothelial cells (PMVECs), upregulated in a rat model of PAH and modulates susceptibility to apoptosis. Our preliminary data also indicate that increased AQP1 protein is associated with elevated β-catenin expression, a protein that regulates migratory, proliferative and survival responses. The mechanism by which AQP1 regulates β-catenin levels is currently unknown; we have generated exciting data indicating a critical role for a specific region of the AQP1 C-terminal tail. This region contains a previously unrecognized putative binding site for GSK3β, an endogenous regulator of β-catenin abundance. Based on these data, we hypothesize that in PAH PASMCs and PMVECs, increased AQP1 levels contribute to cell growth and survival by sequestering GSK3β and reducing its activity/nuclear localization; as a consequence, β-catenin accumulates, promoting migration and proliferation and preventing apoptosis. The Aims of this study are to: 1) determine whether AQP1 regulates β-catenin via binding to GSK3β; 2) identify the mechanism by which AQP1 facilitates cell growth and survival; and 3) evaluate whether cell-specific disruption of AQP1 prevents or reverses PAH.

项目摘要 肺动脉高压（PAH）是一种无法治愈的严重衰弱性疾病。形态测定 研究表明，肺动脉高压的发生与肺动脉的结构性变化有关， 小肺动脉重塑，特征为内皮和平滑肌增厚 细胞层和闭塞性病变的形成。除了血管的增殖和迁移增加外， 细胞，适当的凋亡失败（即，细胞凋亡抵抗）通过缺乏细胞凋亡促进重塑。 周转我们的实验室确定了一个新的候选人作为肺动脉平滑肌细胞的调节剂 （PASMC）功能：水通道蛋白（AQP）。水通道蛋白是形成跨膜通道的蛋白质家族 促进水进出细胞的运输。我们有证据表明，水通道蛋白1（AQP1）， 鉴定的家族成员，在PASMC和肺微血管内皮细胞（PMVEC）中表达， 在PAH大鼠模型中上调并调节对凋亡的易感性。我们的初步数据还显示 AQP1蛋白的增加与β-catenin表达的升高有关，β-catenin是一种调节 迁移、增殖和生存反应。AQP1调节β-catenin水平的机制是 目前未知;我们已经产生了令人兴奋的数据，表明AQP1特定区域的关键作用 C末端尾部该区域含有一个以前未被识别的假定的GSK 3 β结合位点， β-连环蛋白丰度的调节剂。基于这些数据，我们假设在PAH PASMC和PMVEC中， 增加的AQP1水平通过隔离GSK 3 β并降低其活性， 活性/核定位;因此，β-连环蛋白积累，促进迁移和增殖 和防止细胞凋亡。本研究的目的是：1）确定AQP1是否通过调节β-catenin 与GSK3 β结合; 2）确定AQP1促进细胞生长和存活的机制;以及3） 评估AQP1的细胞特异性破坏是否预防或逆转PAH。