Surfactant protein C (SP-C) is exclusively synthesized by pulmonary type II epithelial cells which process the proprotein to the hydrophobic mature peptide for secretion into the alveolar airspace. Mutations in the SP-C gene were recently linked to familial and sporadic interstitial lung disease. The results of our preliminary studies indicate that expression of a disease-associated SP-C mutation in type II epithelial cells of transgenic mice leads to epithelial cell death and profoundly perturbed lung morphogenesis strongly suggesting that mutations in the SP-C gene can cause lung disease. The central hypothesis of this application is that mutations in the SP-C gene result in misfolding of the proprotein and saturation of the ERAD pathway leading to accumulation of a cytotoxic form of the protein. Four specific aims are proposed to test the following hypotheses: (1) The inability to rapidly degrade mutant proSP-C via ERAD results in accumulation of a cytotoxic form of the proprotein; (2) Novel ERAD proteins are involved in the detection and/or degradation of mutant proSP-C; (3) A quality control receptor specifically detects mutant proSP-C and sorts the proprotein for degradation via the ubiquitin-proteasome pathway; and (4) Augmentation of ERAD in vivo will accelerate degradation of mutant proSP-C, thereby preventing/reducing mutant proSP-C induced lung dysmorphogenesis. The long term goal of this work is to identify proteins that selectively enhance ERAD for use as potential therapeutic targets in diseases associated with protein misfolding.