Molecular Targets for Drug Discovery in IPF

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DESCRIPTION (provided by applicant): IPF is a lethal disease leading to death by suffocation due to the relentless accumulation of fibroblasts and their connective tissue products in the alveolar wall. As each alveolus is afflicted by the disease process, there is a pernicious collaboration of innate immunity, epithelial cell death and fibroproliferation simulating the events observed in injury -- except in IPF the injury never heals. In an effort to arrest this progressive disease, here we focus on the fibroproliferative process itself, and its key cellular constituent the myofibroblast. One striking difference between myofibroblasts from fibrotic lesions and those from integumentary and visceral wounds that heal normally is the failure of fibrotic myofibroblasts - in contrast to their normal counterparts - to undergo timely apoptosis. Therefore, we hypothesize that regulatory constituents of the apoptotic cascade that result in aberrant myofibroblast persistence will be candidate molecular targets for antifibrotic drug discovery. Our objective is to develop therapeutics designed to undermine the pathological failure of myofibroblasts in the IPF lung to undergo apoptosis, and restore physiological sensitivity to proapoptotic cues in evolving fibrotic lesions. We plan to achieve our objective through 2 specific aims. Aim 1: Synthesize and evaluate compounds hitting the cap-binding pocket of eukaryotic translation initiation factor 4E (eIF4E), a bonafide molecular target controlling the translation of mRNA encoding key regulators of fibroblast apoptosis. Aim 2: Explore potential molecular targets for antifibrotic drug discovery along apoptotic pathways regulated by the extracellular matrix. If successful, our work will confirm or refute eIF4E as an antifibrotic therapeutic target, and potentially lead to the identification of new IPF specific molecular targets for antifibrotic drug discovery.