Role of TGF-Alpha in Pulmonary Vascular Disease

TGF-α 在肺血管疾病中的作用

• 批准号: 7022907
• 负责人: TIMOTHY DAVID LE CRAS
• 金额: $ 36.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-10 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022907
• 关键词: age difference; angiogenesis; autocrine; epidermal growth factor; gene expression; genetically modified animals; growth factor receptors; growth inhibitors; laboratory mouse; lung development; paracrine; pathologic process; pulmonary artery; pulmonary hypertension; receptor expression; respiratory epithelium; tetracyclines; transforming growth factors; vascular endothelial growth factors

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.

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着重要作用。 虽然临床研究表明转化生长因子-α (TGF-α) 与这些疾病的发病机制有关，但 TGF-α 的作用、其细胞靶标以及所涉及的信号通路尚不清楚。 本申请附带的初步数据表明，早在 2 周龄的转基因小鼠中，TGF-α 的上皮表达就会导致肺动脉数量、血管重塑和肺动脉高压的严重减少。 我们还有初步证据表明，这部分是由远端上皮细胞上 EGF 受体的自分泌信号传导以及血管内皮生长因子-A (VEGF-A) 的减少介导的。 该提案将使用体外和体内方法来测试中心假设，即 TGF-α 的上皮表达会破坏血管生长，并通过 EGF 受体依赖性自分泌-旁分泌信号传导引起血管重塑和肺动脉高压。 在第一阶段，我们将定义肺生长何时被 TGF-α 破坏、TGF-α 的急性或慢性表达是否必要，以及 TGF-α 是否会导致血管重塑和肺动脉高压，而与血管生长的减少无关（具体目标 1） ）。在第二阶段，我们将定义通过上皮的间接信号传导与向血管内皮的直接信号传导（具体目标 2）的作用，使用显性失活（突变）EGF 受体来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 破坏肺血管生长并引起肺动脉高压和血管重塑的时间、细胞靶标和机制。 这些信息将作为制定旨在改善早产儿和成人肺部生长和预防肺动脉高压的治疗策略的基础。