PROPOSAL ABSTRACT Late gestation fetal lung development requires coordinated controls of type II cell proliferation and differentiation. While much progress has been made in determining the mechanisms controlling fetal type II cell differentiation, relatively little is known about the control of fetal type II cell proliferation and the mechanisms which coordinate these two important developmental processes. This proposal is focused on ErbB receptor signaling mechanisms as controlling elements in fetal type II cell proliferation. The ErbB receptor family is comprised of four members: the Epidermal Growth Factor Receptor (EGF-R), ErbB2, ErbB3, and ErbB4. Through a system of different ligands and different receptor dimer formation these receptors orchestrate diverse signaling responses to act as important regulators of cell proliferation and differentiation, especially during development. We have shown the importance of this system in type II cell differentiation. A paradigm of developmental cell biology is that cell proliferation and differentiation are in mechanistic tension, such that up regulation of one process is associated with down regulation of the other process. In this proposal our hypothesis is that ErbB receptor activation mediates fetal lung type II cell growth and differentiation, through diversification of receptor responses. We will address three Specific Aims: #1: Mechanisms controlling type II cell growth versus differentiation are controlled by differential ErbB receptor activity;#2: The mechanisms controlling fetal type II cell growth and differentiation utilize ErbB receptor dimers specific to each process;and #3: Determine the role of ErbB receptor nuclear localization in regulating fetal type II cell growth and differentiation. New insight into the mechanisms controlling fetal type II cell growth will contribute to our ability to develop new therapeutic strategies that will promote normal lung development following preterm birth or other developmental lung diseases.
Premature birth disrupts the growth and development of the lung, especially of specialized lung epithelial cells called type 2 cells, causing significant diseases such as the Respiratory Distress Syndrome and Bronchopulmonary Dysplasia, the leading causes of morbidity and mortality following preterm birth. This project will identify the mechanisms controlling growth and function of immature and mature type 2 cells by studying how ErbB receptor proteins regulate fetal type 2 cell growth and differentiation. The results from this study will provide a platform for developing novel treatments to relieve the burden of RDS and BPD.
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