PAF and Hypoxia-Induced Pulmonary Hypertension

PAF 和缺氧引起的肺动脉高压

• 批准号: 6908146
• 负责人: J. Usha RAJ
• 金额: $ 35.39万
• 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/6908146
• 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（由申请方提供）：本提案的总体目标是研究血小板活化因子（PAF）在慢性缺氧诱导的肺动脉高压（PH）相关肺血管变化中的作用。我们以前已经表明，在胎儿肺血管平滑肌（PVSMC），在缺氧条件下，PAF合成和PAF受体（PAF-R）的表达是高的，这是下调出生时与氧合。我们的主要假设是，在胎儿缺氧环境中，PAF在维持高肺血管张力方面发挥生理作用，并可能有助于血管生长;然而，在慢性缺氧、子宫内或新生儿期，存在过度的PAF介导的信号传导，导致PVSMC和外膜成纤维细胞（AF）增生以及血管重塑和异常血管收缩，从而导致肺动脉高压。具体目标是：1.证明PAF在新生小牛慢性缺氧诱导的肺动脉高压以及PAF受体敲除和过表达转基因小鼠中的作用。2.探讨缺氧条件下PAF对肺血管平滑肌和外膜成纤维细胞的作用机制。具体而言，我们将确定的信号转导途径，PAF与其受体在缺氧导致SMC收缩; PAF刺激PVSMC和AF在缺氧增殖的机制和PAF诱导的成纤维细胞转分化为肌成纤维细胞的机制。这些实验将使我们了解PAF介导的慢性缺氧肺血管重构和血管收缩的机制。从我们的研究结果应该增加我们的理解，PAF有助于慢性缺氧诱导的PH的发病机制的细胞机制。这应该使我们能够开发更好的方法，预防和治疗PH。