Role of TGF-Alpha in Pulmonary Vascular Disease

描述（由申请人提供）： 肺动脉高压在包括支气管肺发育不良在内的许多急性和慢性肺部疾病的发病率和死亡率中起主要作用。 虽然临床研究表明转化生长因子-α（TGF-α）参与了这些疾病的发病机制，但TGF-α的作用、其细胞靶点和所涉及的信号通路尚不清楚。 伴随本申请的初步数据表明，TGF-α的上皮表达早在2周龄时就在转基因小鼠中引起肺动脉数目、血管重塑和肺动脉高压的严重减少。 我们也有初步的证据表明，这是介导的自分泌信号通过表皮生长因子受体在远端上皮细胞，血管内皮生长因子-A（VEGF-A）的减少。 使用在体外和体内的方法，这个建议将测试的核心假设，上皮细胞表达的TGF-α破坏血管生长，并通过EGF受体依赖性自分泌-旁分泌信号引起血管重塑和肺动脉高压。 在第一阶段，我们将确定肺生长何时被TGF-α破坏，TGF-α的急性或慢性表达是否是必要的，以及TGF-α是否独立于血管生长的减少而引起血管重塑和肺动脉高压（具体目标1）。在第二阶段，我们将定义通过上皮细胞的间接信号传导与直接信号传导到血管内皮细胞（特异性目标2）的作用，使用显性负（突变）EGF受体阻断特定细胞区室中的TGF-α信号传导。 在第三阶段，我们将确定TGF-α是否在体外和体内调节II型上皮细胞中VEGF-A的表达，以及VEGF-A的减少是否有助于肺血管疾病的发病机制（具体目标3）。 该提案的总体目标是确定TGF-α干扰肺血管生长并导致肺动脉高压和血管重塑的时间、细胞靶点和机制。 这些信息将作为制定治疗策略的基础，旨在改善早产儿和成人的肺生长和预防肺动脉高压。

DESCRIPTION (provided by applicant): Pulmonary hypertension plays a major role in the morbidity and mortality of a number of acute and chronic lung diseases including bronchopulmonary dysplasia. While clinical studies have implicated transforming growth factor-alpha (TGF-alpha) in the pathogenesis of these diseases, the role of TGF-alpha, its cellular targets, and the signaling pathways involved are unclear. Preliminary data accompanying this application demonstrate that epithelial expression of TGF-alpha causes severe reductions in pulmonary artery number, vascular remodeling, and pulmonary hypertension as early as 2 weeks of age in transgenic mice. We also have preliminary evidence to suggest that this is mediated in part by autocrine signaling through EGF receptors on distal epithelial cells, and reductions in vascular endothelial growth factor-A (VEGF-A). Using both in vitro and in vivo approaches, this proposal will test the central hypothesis that epithelial expression of TGF-alpha disrupts vascular growth and causes vascular remodeling and pulmonary hypertension through EGF receptor-dependent autocrine-paracrine signaling. In the first phase we will define when pulmonary growth is disrupted by TGF-alpha, whether acute or chronic expression of TGF-alpha is necessary, and whether TGF-alpha causes vascular remodeling and pulmonary hypertension independent of reductions in vascular growth (Specific Aim 1). In the second phase we will define the role of indirect signaling through the epithelium versus direct signaling to the vascular endothelium (Specific Aim 2) using a dominant negative (mutant) EGF receptor to block TGF-alpha signaling in specific cellular compartments. In the third phase we will define whether TGF-alpha, regulates expression of VEGF-A in type II epithelial cells in vitro and in vivo, and whether reductions in VEGF-A contribute to the pathogenesis of pulmonary vascular disease (Specific Aim 3). The overall goal of this proposal is to define the timing, cellular targets, and mechanism by which TGF-alpha disrupts pulmonary vascular growth and causes pulmonary hypertension and vascular remodeling. This information will serve as a basis for developing therapeutic strategies aimed at improving lung growth and preventing pulmonary hypertension in premature babies and adults.