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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060165-04
Application #
6476863
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Berberich, Mary Anne
Project Start
2000-12-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2002
Total Cost
$274,917
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106