Peroxisome proliferator-activated receptor gamma (PPAR() is an anti-inflammatory molecule in various tissue systems including the lung. Its functional role in the lung is not well understood. The long-term goal of this work will determine PPAR( molecular pathways in lung pathogenesis. The central hypothesis for the proposed studies is that PPAR( is a mediator of pulmonary inflammation via the molecular control of matrix metalloproteinase-12 (MMP-12) and that this control derives from fatty acid ligands, generated in the lysosomes by lysosomal acid lipase (LAL). This has been supported by our previous study that blockage of its ligand synthesis in lysosomal acid lipase deficient mice (lal-/-) caused pulmonary inflammation, emphysema, unwanted epithelial cell growth and aberrant gene expression. Treatment with PPAR( ligands 9-HODE and Ciglitazone significantly attenuated lal-/- pulmonary inflammation and aberrant gene expression. The ligands and PPAR( negatively regulate MMP-12 promoter activity in in vitro transient transfection assays. The PPAR( protein is primarily detected in broncho-alveolar macrophages, Clara cells and alveolar type II epithelial cells in the lung. Thus, the central hypothesis will be tested in our two new transgenic models, in which endogenous PPAR( is inactivated by over-expression of its dominant negative form (dnPPAR() in alveolar type II epithelial cells or bronchoalveolar macrophages in doxycycline-inducible transgenic mouse system. Preliminary assessment of a transgenic model, in which dnPPAR( was over- expressed for 2 months under the control of the CCSP promoter, showed inflammatory cell influx into the lung and emphysema. In addition, the expression level of MMP12 increased 55-fold in the dnPPAR( transgenic mice. The long-term pathogenic effect of dnPPAR( over-expression has not been determined.
Three specific aims are designed to test the central hypothesis:
Specific Aim 1 : Determine pathogenesis of dnPPAR( in respiratory epithelial cells;
Specific Aim 2 : Determine pathogenesis of dnPPAR( in macrophages;
Specific Aim 3 : Determine molecular mechanism of MMP12 regulation in lung epithelial cells. Together, these studies will significantly enhance our knowledge for understanding the pathophysiological function of PPAR( in the lung, especially in pulmonary inflammation and tissue remodeling, and elucidate the molecular mechanism of gene regulation in MMP12 that mediates the phenotype in the lung of lal-/- mice. The outcomes of these studies will provide evidence to design new strategies to combat pulmonary inflammation and emphysema. PROJECT NARRATIVE: The objectives of this research proposal are to understand the critical role of peroxisome proliferator- activated receptor gamma (PPAR() as anti-inflammatory effector in the lung. We are using the state-of-art techniques to create transgenic mice that have cell specific and temporal regulated expression of dominant negative form of PPAR( (dnPPAR() in pulmonary cells (alveolar type II epithelial cells or bronchio-alveolar macrophages) and characterizing their pulmonary inflammation, remodeling, and emphysema phenotype. In addition, the proposed studies will elucidate the molecular linker of inactivation of PPAR( and the remodeling and emphysema phenotype through transcriptional regulation of matrix metallproteinase-12 (MMP-12) gene. Together, these studies will significantly enhance our knowledge for understanding the pathophysiological function of PPAR( in the lung, especially in pulmonary inflammation and tissue remodeling. These studies will provide new approaches to design strategies and discover drugs to combat emphysema and COPD. ? ? ?
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