PPAR gamma Signaling and Lung Fibroblast Transdifferentiation

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DESCRIPTION (provided by applicant): Abnormal injury/repair, with truncation of alveolarization, is the major histopathological hallmark of "The New Bronchopulmonary Dysplasia (BPD)". We have recently proposed that disrupting normal homeostatic epithelial-mesenchymal communications, and the consequent alveolar interstitial fibroblast (AIF)-to-myofibroblast (MYF) transdifferentiation, are the key events in its pathobiology. The specific molecular mechanisms involved in this process remain incompletely defined. The objective of this proposal is to determine the specific molecular mechanisms involved in BPD, particularly the role of Peroxisome Proliferator Activated Receptor (PPAR) signaling in hyperoxia-induced rat lung AIF-to-MYF transdifferentiation, using both in vivo and in vitro models and to determine the effectiveness of a novel molecular preventive and therapeutic approach. In Specific Aim 1, using Laser Capture Microdissection, Morphometry, Immunohistochemistry, Real Time-PCR, Northern, and Western analyses, we will determine, in an in vivo neonatal rat model, how PPAR agonists prevent and/or treat hyperoxia-induced AIF-to-MYF transdifferentiation. In Specific Aim 2, using Real Time -PCR, Northern and Western analyses, Metabolomics, Antisense, and Transfection in vitro studies, for the mRNA expression of Parathyroid Hormone-related Protein Receptor, PPAR, C/Enhancer Binding Protein, and Adipocyte Differentiation Related Protein, coupled with the differential expression and phosphorylation of the corresponding proteins, we will determine the mechanism involved in AIF-to-MYF transdifferentiation. We will also determine how AIF-to-MYF transdifferentiation can be prevented or reversed by stimulating the lipogenic pathway through potent PPAR ligands such as rosiglitazone and GW7845. This proposal, in addition to providing new insights into the pathobiology of BPD, has enormous potential for opening up novel interventional strategies to tackle chronic lung disease in general, and BPD in particular. In fact, using the functional genomic approach, adopted in our proposal, i.e., inducing lipogenic transcription factors, may not only prevent, but may also reverse established chronic lung disease. The concept put forward in this proposal is novel, innovative, and departs from the traditional paradigm of oxygen-induced lung damage, and may have much wider implications than simply understanding oxygen-induced lung injury.