HER RECEPTOR FAMILY, HEREGULIN AND LUNG DEVELOPMENT

生长因子受体的鉴定及其特异性激活 参与肺发育的配体可能通过以下方式帮助疾病管理 为新药提供新的治疗方法和靶点。在……里面 在之前的研究中，我的实验室发现了一种新的生长因子 人肺中的受体--人表皮生长因子受体 2(HER2)。该受体是四个膜家族的成员之一。 结合受体酪氨酸激酶(RTK)称为HER1、HER2、HER3和HER4。 它们与一种名为heregine的特定激活配体的相互作用 (HRG)在调节上皮细胞生长和 差异化。我们的进一步研究表明，HER2、HER3和HRG 在发育中的人、小鼠和大鼠的肺中表达，是暂时的 可能在正常的肺发育中起着重要作用。它 是这项研究的总体目标是确定其生物学作用 HRG/HER系统在肺发育和肺功能调节中的作用 上皮细胞增殖。具体地说，这项提议假设 1)高亲和力HRG受体(HER2/HER3)的激活 异源二聚体)通过其配体(HRG)导致增殖信号 肺上皮细胞，2)高亲和力HRG的激活 肺上皮细胞中的受体启动特定的信号 肺上皮细胞必需的转导级联反应 生长和分化，以及3)HRG/高亲和力的调节 体内的HRG受体会导致肺的正常发育不足。 我们将通过以下方式检验这一假设：1)确定角色激活 高亲和力的HRG受体，HER2/HER3异源二聚体，在人类 胎儿肺的体外发育，2)确定信号级联 HRG诱导肺上皮细胞HER活化后启动 细胞，以及3)开发肺特异的转基因小鼠品系， 发育不适当的HRG表达，或显性阴性HRG 用于确定异常HRG受体的发育效应的受体 活体激活对肺生长发育的影响。这些研究将 使用人胎肺外植体模型系统进行体外实验 肺上皮细胞株的建立，以及在体内的发展 转基因小鼠品系。

Identification of growth factor receptors and their specific activating ligands involved in lung development might aid in disease management by providing novel therapeutic approaches and targets for new drugs. In previous studies, my laboratory identified a novel growth factor receptor in the human lung, the human epidermal growth factor receptor 2 (HER2). This receptor is one member of a family of four membrane bound receptor tyrosine kinases (RTK) called HER1, HER2, HER3 and HER4. Their interaction with a specific activating ligand called heregulin (HRG) is important in the regulation of epithelial cell growth and differentiation. Our further studies showed that HER2, HER3 and HRG are expressed in the developing human, murine and rat lung, are temporally modulated, and are probably important in normal lung development. It is the overall goal of this study to ascertain the biological role of the HRG/HER system in the regulation of lung development and pulmonary epithelial cell proliferation. Specifically, this proposal hypothesizes that: 1) Activation of the high affinity HRG receptor (HER2/HER3 heterodimer) by its ligand (HRG) results in a proliferative signal for pulmonary epithelial cells, 2) Activation of the high affinity HRG receptor in pulmonary epithelial cells initiates a specific signal transduction cascade that is essential for pulmonary epithelial cell growth and differentiation, and 3) Modulation of the HRG/high affinity HRG receptor in vivo will result in lack of normal lung development. We will test this hypothesis by: 1) Determining the role activation of the high affinity HRG receptor, the HER2/HER3 heterodimer, has in human fetal lung development in vitro, 2) Defining the signal cascade initiated after HRG-induced HER activation in pulmonary epithelial cells, and 3) Developing transgenic mouse strains with lung-specific, developmentally inappropriate HRG expression, or a dominant-negative HRG receptor to determine the developmental effect of aberrant HRG receptor activation on lung growth and development in vivo. These studies will be performed in vitro using a human fetal lung explant model system and pulmonary epithelial cell lines, and in vivo with the development of transgenic mouse strains.