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、慢性肺部疾病的发病率和死亡率中起主要作用。尽管临床研究表明转化生长因子-α与这些疾病的发病机制有关，但转化生长因子-α的作用、其细胞靶点以及所涉及的信号通路尚不清楚。伴随这项应用的初步数据表明，转化生长因子-α的上皮表达在2周大的转基因小鼠中就能导致肺动脉数量、血管重构和肺动脉高压的严重减少。我们也有初步证据表明，这在一定程度上是通过远端上皮细胞上EGF受体的自分泌信号和血管内皮生长因子-A(VEGF-A)的减少来调节的。利用体外和体内两种方法，这一建议将检验这一中心假设，即上皮细胞中转化生长因子-α的表达通过EGF受体依赖的自分泌-旁分泌信号扰乱血管生长，导致血管重塑和肺动脉高压。在第一阶段，我们将确定转化生长因子-α破坏肺生长的时间，转化生长因子-α的急性或慢性表达是必要的，以及转化生长因子-α是否独立于血管生长减少而导致血管重塑和肺动脉高压(特定目标1)。在第二阶段，我们将使用显性的负性(突变型)EGF受体来阻断特定细胞间隔中的转化生长因子-α信号，从而确定通过上皮的间接信号与血管内皮细胞的直接信号的作用(特定目标2)。在第三阶段，我们将确定转化生长因子-α是否在体外和体内调节II型上皮细胞中血管内皮生长因子-A的表达，以及血管内皮生长因子-A的减少是否在肺血管疾病的发病机制中起作用(特定目标3)。这项建议的总体目标是确定转化生长因子-α破坏肺血管生长并导致肺高压和血管重塑的时机、细胞靶点和机制。这些信息将作为制定旨在改善早产儿和成人肺生长和预防肺动脉高压的治疗策略的基础。

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.