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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL061646-06
Application #
6889788
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$290,083
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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