Aquaporin 1 and pulmonary hypertension

水通道蛋白 1 和肺动脉高压

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：肺动脉高压是一种严重使人衰弱的疾病，无法治愈。形态计量学研究表明，肺动脉高压的发展与小肺动脉的结构重塑有关，其特征是平滑肌细胞层的增厚和新肌肉在以前非乳房前毛皮前动脉周围延伸。虽然前者被认为是由于肺动脉平滑肌细胞（PASMC）肥大，增生和对凋亡的抗性，但后者被认为是由PASMC迁移引起的。我们的实验室将新候选人确定为PASMC迁移，增殖和生存的调节者：Aquaporins（AQPS）。 AQP是形成跨膜通道的蛋白质家族，可促进水进入和流出细胞。我们有证据表明，aquaporin 1（AQP1）（AQP1）是第一个家庭成员，在PASMC中表达，由缺氧诱导，PASMC迁移和增殖所必需。此外，我们产生了令人兴奋的数据，表明在控制这些细胞过程中，AQP1 C末端尾部（而不是水传输）至关重要。我们的初步数据还表明，升高的AQP1蛋白与``Atenin表达''相关，Atenin表达是一种调节PASMC中迁移，增殖和存活反应的蛋白质。 AQP1如何调节``ATENIN水平''是未知的，但是我们表明需要AQP1细胞质尾巴。最后，尽管我们有充分的证据表明AQP1在介导PASMC迁移和增殖中起着至关重要的作用，但AQP1是否有助于血管重塑和pH的发展。这是这项研究的目标是：1）阐明缺氧在PASMC中上调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是否在支持肺动脉高压中起作用。