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（由申请人提供）：肺动脉高压是一种严重使人衰弱的疾病，无法治愈。形态测量研究表明，肺动脉高压的发生与肺小动脉的结构重塑有关，其特征是平滑肌细胞层增厚以及先前非肌性毛细血管前小动脉周围新肌肉的延伸。前者被认为是由于肺动脉平滑肌细胞（PASMC）肥大、增生和抗凋亡所致，而后者被认为是由于PASMC迁移所致。我们的实验室确定了一种新的候选药物作为 PASMC 迁移、增殖和存活的调节剂：水通道蛋白 (AQP)。 AQP 是一个蛋白质家族，可形成跨膜通道，促进水进出细胞。我们有证据表明，水通道蛋白 1 (AQP1) 是第一个被识别的家族成员，在 PASMC 中表达，由缺氧诱导，并且是 PASMC 迁移和增殖所必需的。此外，我们生成了令人兴奋的数据，表明 AQP1 C 末端尾部（而不是水运输）在控制这些细胞过程中发挥着关键作用。我们的 初步数据还表明，AQP1 蛋白增加与 atenin 表达升高相关，atenin 是一种调节 PASMC 迁移、增殖和生存反应的蛋白。 AQP1 如何调节 atenin 水平尚不清楚，但我们表明 AQP1 细胞质尾是必需的。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 的发展仍然未知。因此，本研究的目的是：1）阐明缺氧上调PASMCs中AQP1的机制； 2) 确定 AQP1 调节 atenin 表达的机制，并确定 AQP1 介导的细胞功能变化是否需要 atenin； 3)确定AQP1是否在促进肺动脉高压中发挥作用。