Aquaporin 1 and pulmonary hypertension

水通道蛋白 1 和肺动脉高压

• 批准号: 9187956
• 负责人: Larissa A. Shimoda
• 金额: $ 40.5万
• 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 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187956
• 关键词: AQP1 gene; Apoptosis; Binding; Binding Sites; Biological Assay; Blood Vessels; C-terminal; Cell Adhesion; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular biology; Chemicals; Chronic; Co-Immunoprecipitations; Complex; Confocal Microscopy; Cytoplasmic Tail; Data; Development; Disease; Dissociation; Family member; Focal Adhesions; Gene Activation; Genetic Transcription; Glycogen Synthase Kinase 3; Goals; Growth; Hyperplasia; Hypertrophy; Hypoxia; In Vitro; Laboratories; Link; Lung; Mediating; Messenger RNA; Molecular; Molecular Biology; Mus; Muscle; Nuclear Translocation; Patients; Permeability; Play; Protein Family; Protein-Serine-Threonine Kinases; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Regulation; Resistance; Role; Signal Pathway; Smooth Muscle Myocytes; Tail; Techniques; Testing; Time; Translations; Up-Regulation; Vascular Smooth Muscle; Vascular remodeling; Water; Work; arteriole; base; cell motility; experimental study; hypoxia inducible factor 1; knock-down; migration; novel; novel therapeutics; overexpression; paralogous gene; pressure; primary pulmonary hypertension; protein degradation; protein expression; public health relevance; response; transcription factor; vasoconstriction; water channel

DESCRIPTION (provided by applicant): Pulmonary hypertension is a severely debilitating disease with no cure. Morphometric studies revealed that the development of pulmonary hypertension is associated with structural remodeling of the small pulmonary arteries, characterized by thickening of the smooth muscle cell layer and extension of new muscle around previously non-muscular precapillary arterioles. While the former is thought to be due to pulmonary arterial smooth muscle cell (PASMC) hypertrophy, hyperplasia and resistance to apoptosis, the latter is believed to result from PASMC migration. Our laboratory identified a new candidate as a regulator of PASMC migration, proliferation and survival: 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, induced by hypoxia and required for PASMC migration and proliferation. Moreover, we have generated exciting data indicating a critical role for the AQP1 C-terminal tail, but not water transport, in controlling these cellular processes. Our preliminary data also indicate that increased AQP1 protein is associated with elevated �atenin expression, a protein that regulates migratory, proliferative and survival responses in PASMCs. How AQP1 regulates �atenin levels is unknown, but we show that the AQP1 cytoplasmic tail is required. Finally, while we have strong evidence that AQP1 plays a critical role in mediating PASMC migration and proliferation, whether AQP1 contributes to the development of vascular remodeling and PH remains unknown. Thus, the goals of this study are to: 1) elucidate the mechanism by which hypoxia upregulates AQP1 in PASMCs; 2) identify the mechanism by which AQP1 modulates �atenin expression and determine whether �atenin is required for AQP1-mediated changes in cell function; and 3) determine whether AQP1 plays a role in facilitating pulmonary hypertension.

描述(申请人提供)：肺动脉高压是一种无法治愈的严重衰弱的疾病。形态计量学研究表明，肺动脉高压的发展与小动脉的结构重建有关，其特征是平滑肌细胞层增厚，并在原有的非肌性毛细血管前小动脉周围新生肌肉。前者被认为是由于肺动脉平滑肌细胞(PASMC)肥大、增殖和抗凋亡所致，后者则被认为是PASMC迁移的结果。我们的实验室发现了一种新的PASMC迁移、增殖和存活调节因子：水通道蛋白(AQPs)。水通道蛋白是一种形成跨膜通道的蛋白质家族，可促进水的进出细胞。我们有证据表明，第一个被发现的家族成员水通道蛋白1(Aquaporin 1，AQP1)在PASMC中表达，由低氧诱导，是PASMC迁移和增殖所必需的。此外，我们还产生了令人兴奋的数据，表明AQP1C-末端尾巴在控制这些细胞过程中发挥了关键作用，但不是水运输。我们的 初步数据还表明，AQP1蛋白的增加与�atenin的表达增加有关，AQP1atenin是一种调节PASMC的迁移、增殖和生存反应的蛋白质。水通道蛋白1如何调节�atenin水平尚不清楚，但我们发现水通道蛋白1的胞质尾巴是必需的。最后，虽然我们有强有力的证据表明AQP1在介导PASMC迁移和增殖中发挥关键作用，但AQP1是否有助于血管重塑和PH的发展仍不清楚。因此，本研究的目的是：1)阐明缺氧上调PASMC中AQP1的机制；2)确定AQP1调节�atenin表达的机制，并确定�atenin是否是AQP1介导的细胞功能改变所必需的；以及3)确定AQP1是否在促进肺动脉高压中发挥作用。