The goal of this application is to develop better understanding of the mechanism of fibroblast-type II cell communication which regulate the development of surfactant synthesis. The investigators have shown that the epidermal growth factor and its receptor (EGFR) control the initiation of this communication, while dihydrotestosterone (DHT) and transforming growth factor beta (TGF beta) inhibit it. Dr. Nielsen has recently gained new insight to the elements of this process, showing that other members of the EGF family are important to this process. He proposes to identify the molecular mechanisms of fibroblast-type II cell communication, including their positive and negative regulation. He hypothesizes that EGFR activation in fetal lung fibroblasts stimulates production of neuregulin (NRG) which activates ErbB-2 receptors on type II cells to stimulate surfactant synthesis. Furthermore, DHT and TGF beta inhibit this pathway.
The Specific Aims to be tested are that 1) the mechanisms of fibroblast-type II cell communication are controlled by specific ErbB receptor expression , dimerization and trafficking in fetal lung fibroblasts and type II cells during development and identify which dimers in fibroblasts induce fibroblast-type II cell communication, and which dimers in type II cells stimulate surfactant synthesis; 2) EGF-R activation positively regulates fibroblast-type II cell communication by stimulating fibroblasts to produce NRG, which then induces surfactant synthesis. They will study the effect of upregulation and inhibition of EGF-R activation on NRG production, and inhibit NRG production to test if this removes the ability of EGF-R activation to induce fibroblast-type II cell communication; 3) DHT and TGFbeta down regulate specific elements of ErbB receptor activation and NRG production, disrupting fibroblast-type II cell communication. They will study the effects of DHT and TGFbeta on ErbB receptor expression and activation in fibroblasts and type II cells, on NRG production by fetal lung fibroblasts, and stimulation of surfactant synthesis in type II cells. These studies are expected to provide significant new insights to the mechanisms regulating surfactant synthesis in the fetal lung and make important contributions towards developing new strategies for preventing and treating RDS.
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