PAF and Hypoxia-Induced Pulmonary Hypertension

PAF 和缺氧引起的肺动脉高压

• 批准号: 7081273
• 负责人: J. Usha RAJ
• 金额: $ 34.56万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081273
• 关键词: biological signal transduction; cell proliferation; confocal scanning microscopy; cow; cytokine receptors; embryo /fetus hypoxia; fibroblasts; gene targeting; genetically modified animals; hyperplasia; in situ hybridization; laboratory mouse; phosphorylation; platelet activating factor; polymerase chain reaction; pulmonary circulation; pulmonary hypertension; receptor expression; vascular smooth muscle; vasomotion

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the role of platelet activating factor (PAF) in the lung vascular changes associated with chronic hypoxia-induced pulmonary hypertension (PH). We have previously shown that in fetal pulmonary vascular smooth muscle (PVSMC), under hypoxic conditions, PAF synthesis and PAF receptor (PAF-R) expression are high, and that this is down regulated at birth with oxygenation. Our main hypothesis is that in the hypoxic environment of the fetus, PAF plays a physiological role in maintaining high pulmonary vasomotor tone and may contribute to vascular growth; however, in chronic hypoxia, in utero or in the newborn period, there is excessive PAF-mediated signaling leading to PVSMC and adventitial fibroblast (AF) hyperplasia and vascular remodeling and abnormal vasoconstriction resulting in pulmonary hypertension. The specific aims are: 1. To demonstrate a role for PAF in chronic hypoxia-induced pulmonary hypertension in neonatal calves and in PAF-receptor knock-out and over-expressing transgenic mice. 2. To investigate the mechanisms by which PAF, in the presence of hypoxia, mediates its effects in pulmonary vascular smooth muscle and adventitial fibroblasts. Specifically, we will determine the signal transduction pathway by which PAF interactions with its receptor in hypoxia leads to SMC contraction; the mechanisms by which PAF stimulates PVSMC and AF proliferation in hypoxia and the mechanism of PAF-induced trans-differentiation of fibroblasts to myo-fibroblasts. These experiments will enable us to understand the mechanisms of PAF-mediated pulmonary vascular remodeling and vaso-constriction in chronic hypoxia. Results from our studies should increase our understanding of the cellular mechanisms by which PAF contributes to the pathogenesis of chronic hypoxia-induced PH. This should enable us to develop better methods of prevention and treatment of PH.

描述（由申请人提供）：该提案的总体目的是研究血小板激活因子（PAF）在与慢性缺氧诱导的肺动脉高压（pH）相关的肺血管变化中的作用。我们先前已经表明，在低氧条件下，PAF合成和PAF受体（PAF-R）表达中，在胎儿肺血管平滑肌（PVSMC）中，这在氧合产生时被降低。我们的主要假设是，在胎儿的缺氧环境中，PAF在维持高肺血管舒张张张张力方面起生理作用，并可能有助于血管生长。然而，在慢性缺氧，子宫内或新生儿时期，PAF介导的信号传导过多，导致PVSMC和增生成纤维细胞（AF）增生和血管重塑，并引起异常血管收缩，导致肺部高血压。具体目的是：1。证明PAF在慢性缺氧诱导的新生小牛和PAF受体敲除和过表达的转基因小鼠中的作用。 2。研究在缺氧存在下PAF介导其在肺血管平滑肌和外在成纤维细胞中的作用的机制。具体而言，我们将确定PAF与其受体在缺氧中相互作用导致SMC收缩的信号转导途径。 PAF刺激缺氧中PVSMC和AF增殖的机制以及PAF诱导的成纤维细胞向肌成纤维细胞的反式分化的机制。这些实验将使我们能够理解慢性缺氧中PAF介导的肺血管重塑和血管收缩的机制。我们的研究结果应增加对PAF有助于慢性缺氧诱导的pH发病机理的细胞机制的理解。这应该使我们能够开发出更好的pH预防和治疗方法。