Cell-specific Gene Therapy of mTOR in ALI

In this project, we are pursuing an innovative concept that mechanistic target of rapamycin (mTOR), a master regulator of cell growth and metabolism, serves distinct functions depending upon the cellular context (proinflammatory in epithelial and anti-inflammatory in endothelial cells) with an overall effect of proinflammatory phenotype in the lung. Specifically, the project is focused on defining the mechanistic basis of cell-specific role of mTOR in ALI and developing a novel therapeutic strategy that relies on simultaneous but differential cell-specific modulation of mTOR signaling (i.e., increasing it in pulmonary endothelium and at the same time decreasing it in alveolar epithelium) against evolving ALI.To this end, we are using a new and exciting technology developed by our collaborator Dr. David Dean that allows cell-specific transfer of genes and shRNA to endothelial and epithelial cells in the alveoli. It should be emphasized that such a therapeutic intervention cannot be achieved with existing drugs targeting MTOR as they cannot discriminate between different cell types. This is an exciting concept that not only represents a new paradigm but also provides the basis for identification of other molecular signals with differential cell-specific functions in the settings of ALI and other inflammatory diseases for developing similar therapeutic strategies to control them.