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: 6125878
• 负责人: JEFFREY A KERN
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-18 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6125878
• 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