Targeting the Amino Acid Transporter SLC7A5 for Pulmonary Fibrosis

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PROJECT SUMMARY Idiopathic Pulmonary Fibrosis (IPF) constitutes a tremendous burden to public health. IPF is a rapidly progressive lung disease that results from the aberrant accumulation of extracellular matrix proteins (ECM) in fibroblasts with an estimated survival of 3-4 years. Amino acids are required to provide the critical biomass for proliferating fibroblasts. The varied mechanisms controlling amino acid transport and metabolism represent a key opportunity for drug development and precision medicine. SLC7A5 (Solute Carrier Family 7 Member 5) mediates the uptake of essential amino acids primarily leucine and efflux glutamine out of the cell. As leucine is critical for the activation of mTOR and aberrant mTOR activation is a hallmark of pulmonary fibrosis, collectively our preliminary findings motivate our novel hypothesis that SLC7A5 promotes myofibroblast differentiation, mTOR activation, apoptosis and mitophagy resistance and by targeting SLC7A5 which could capable of abrogating multiple facet of fibroblast activation, may represent a efficacious approach towards developing new therapeutic strategies to treat fibroproliferative diseases. These questions will be addressed by 3 highly interrelated Specific Aims. Aim 1. We will define the biological roles, metabolic and molecular mechanism(s) by which SLC7A5 regulate profibrotic TGF-β signaling and whether the induction of apoptosis by inhibiting SLC7A5 “chemosensitize” fibrotic foci. Aim 2. We will elucidate detailed role(s) of SLC7A5 mediated mitochondrial alteration in controlling fibroblast apoptosis and mitophagy. We will also investigate whether SLC7A5 inhibition induces mitophagy and inhibits lung fibrosis development in the setting of insufficient mitophagy as seen in IPF. Aim 3. We will determine the in vivo efficacy of targeting SLC7A5 in a therapeutic model of lung fibrosis and aging. The completion of these specific aims will provide important mechanistic as well as preclinical information on the role(s) of SLC7A5 in mediating the fibroproliferative actions of TGF-β and a new therapeutic approach for the treatment of pulmonary fibrosis.