Aquaporin 1 and 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性疾病。形态计量学研究显示肺动脉高压的发展与肺动脉结构重塑有关，其特征是平滑肌细胞层增厚，新生肌肉在先前非肌肉性毛细血管前小动脉周围延伸。前者被认为是由于肺动脉平滑肌细胞（PASMC）肥大、增生和对凋亡的抵抗，后者被认为是PASMC迁移的结果。我们的实验室发现了一个新的候选者作为PASMC迁移、增殖和存活的调节剂：水通道蛋白（AQPs）。aqp是一个家族的蛋白质，形成跨膜通道，促进水进出细胞的运输。我们有证据表明，水通道蛋白1 （AQP1）是第一个家族成员，在PASMC中表达，由缺氧诱导，是PASMC迁移和增殖所必需的。此外，我们已经获得了令人兴奋的数据，表明AQP1 c末端尾部在控制这些细胞过程中起关键作用，而不是水运输。我们的

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.