The normal lung is chronically exposed to mechanical strain, which affects pulmonary growth and development. In addition, respiratory failure necessitates mechanical ventilation, which induces lung injury. The cellular events resulting from strain in the lung are not well understood. Identifying the mediators of the growth, development and injury triggered by mechanical strain will allow development of therapeutic interventions aimed at mitigating abnormal strain-related effects while enhancing beneficial strain responses. The current proposal focuses on early strain-induced signaling events in pulmonary epithelial cells using a mechanically driven, computer controlled cell culture systems that exposes cells to mechanical strain in vitro, allowing measurements of biochemical and molecular alterations in response to strain. NIH H441 cells, a human pulmonary adenocarcinoma cell line, will be utilized to study the early signaling pathway mediating the proliferative effect of strain on pulmonary epithelial cells. Preliminary data obtained by the principal investigator demonstrate early tyrosine phosphorylation of a 125 kDa protein (SP125) in response to strain. The amino acid sequencing of SP125 will be performed, and the cDNA of this protein cloned. The hypothesis that SP125 regulates strain-induced proliferation, and provide insights into other mediators of lung growth, development, and injury. The principal investigator for this proposal has completed a fellowship in Neonatalogy, and is currently in her third year on the faculty at the University of Rochester. She has demonstrated a commitment to pulmonary basic science research relevant to clinical problems, and has developed a variety of basic science skills related to protein chemistry and cell signaling. The MCSDA will allow her to continue to develop her research career, expand her abilities to investigate cell signaling, and develop her molecular biology background and skills with further laboratory and didactic training. The environment at the University of Rochester includes a critical mass os successful independent investigators in these areas, whose research interests are aligned with those of the principal investigator. The project is designed to optimize the principle investigator's research development, while yielding information regarding pulmonary epithelial responses to mechanical strain.
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