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）是一种严重令人衰弱的疾病，无法治愈。形态计量学 研究表明，肺动脉高压的发展与健壮的结构有关 小肺动脉的重塑，其特征是内皮和平滑肌增厚 细胞层和闭塞病变的形成。除了增加血管增殖和迁移 细胞，适当凋亡（即凋亡耐药性）的失败有助于通过缺乏细胞进行重塑 周转。我们的实验室将新候选者确定为肺动脉平滑肌细胞的调节剂 （PASMC）功能：水通道蛋白（AQPS）。 AQP是形成跨膜通道的蛋白质家族 这有助于水进入和流出细胞。我们有证据表明Aquaporin 1（AQP1），第一个 鉴定出的家庭成员在PASMC和肺微血管内皮细胞（PMVEC）中表达， 在大鼠模型中上调，并调节凋亡的易感性。我们的初步数据也表明 增加的AQP1蛋白与β-catenin的表达升高有关，β-catenin表达是调节的蛋白 迁移，增殖和生存反应。 AQP1调节β-catenin水平的机制为 目前未知；我们生成了令人兴奋的数据，表明AQP1特定区域的关键作用 C末端。该区域包含一个以前未被认可的GSK3β的假定结合位点（一种内生 β-catenin丰度。基于这些数据，我们假设在PAH PASMC和PMVEC中， AQP1水平升高通过隔离GSK3β并减少其生存促进细胞生长和存活 活动/核定位；结果，β-catenin积累，促进迁移和增殖 并防止凋亡。这项研究的目的是：1）确定AQP1是否通过通过 与GSK3β结合； 2）确定AQP1促进细胞生长和存活的机制； 3） 评估AQP1的细胞特异性破坏是否阻止或逆转PAH。