HER RECEPTOR FAMILY, HEREGULIN AND LUNG DEVELOPMENT

她的受体家族、调节蛋白和肺部发育

• 批准号: 6330165
• 负责人: JEFFREY A KERN
• 金额: $ 27.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330165
• 关键词: biological signal transduction; cell growth regulation; cell proliferation; epidermal growth factor; fluorescent in situ hybridization; genetically modified animals; growth factor receptors; heregulin; histogenesis; human fetus tissue; laboratory mouse; polymerase chain reaction; radiotracer; receptor expression; respiratory epithelium; tissue /cell culture; western blottings

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.

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有助于疾病管理， 为新药提供新的治疗方法和靶点。 在 在之前的研究中，我的实验室发现了一种新的生长因子， 人表皮生长因子受体（Human epidermal growth factor receptor） 2（HER2）。 这种受体是四种膜受体家族中的一员， 结合受体酪氨酸激酶（RTK），称为HER 1、HER 2、HER 3和HER 4。 它们与一种叫做heregulin的特殊激活配体相互作用 (HRG)在调节上皮细胞生长中是重要的， 分化 我们的进一步研究表明，HER 2、HER 3和HRG是 在发育中的人、鼠和大鼠肺中表达， 调节，并且可能在正常肺发育中很重要。 它 本研究的总体目标是确定 HRG/HER系统在肺发育和肺功能调节中的作用 上皮细胞增殖 具体而言，该提案假设 1）高亲和力HRG受体（HER 2/HER 3）的活化 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的活化 肺上皮细胞中的受体启动一种特异性信号 肺上皮细胞所必需的转导级联反应 生长和分化，和3）调节HRG/高亲和力 HRG受体在体内的缺失会导致肺发育异常。 我们将通过以下方式来检验这一假设：1）确定 高亲和力HRG受体，HER 2/HER 3异源二聚体，在人类中具有 体外胎肺发育，2）定义信号级联 在HRG诱导的肺上皮HER活化后启动 细胞，和3）开发具有肺特异性， 发育不适当的HRG表达，或显性阴性HRG 受体，以确定异常HRG受体的发育效应 激活对肺生长和发育的影响。 这些研究将 使用人胎肺外植体模型系统在体外进行，并且 肺上皮细胞系，并在体内与发展， 转基因小鼠品系