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PAF and Hypoxia-Induced Pulmonary Hypertension

PAF 和缺氧引起的肺动脉高压

基本信息

批准号：
7649774
负责人：
J. Usha RAJ
金额：
$ 17.21万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-07-31
项目状态：
已结题

项目摘要

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）：本提案的总体目标是研究血小板活化因子（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。我们之前已经表明，在胎儿肺血管平滑肌（PVSMC）中，在缺氧条件下，PAF 合成和 PAF 受体（PAF-R）表达较高，并且在出生时随着氧合作用而下调。我们的主要假设是，在胎儿的缺氧环境中，PAF在维持高肺血管舒缩张力方面发挥着生理作用，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，存在过多的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 在新生犊牛和 PAF 受体敲除和过度表达转基因小鼠中慢性缺氧诱导的肺动脉高压中的作用。 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影响机制。具体来说，我们将确定缺氧时PAF与其受体相互作用导致SMC收缩的信号转导途径；缺氧条件下PAF刺激PVSMC和AF增殖的机制以及PAF诱导成纤维细胞向肌成纤维细胞转分化的机制。这些实验将使我们能够了解 PAF 介导的肺血管重塑和慢性缺氧时血管收缩的机制。我们的研究结果应该会增加我们对 PAF 导致慢性缺氧诱发 PH 发病机制的细胞机制的理解。这将使我们能够开发出更好的预防和治疗 PH 的方法。