Surfactant protein C (SP-C) is a 35 amino acid lung-specific hydrophobic peptide that enhances the biophysical activity of surfactant phospholipid. The importance of SP-C to lung health and disease has been underscored by the observations that heterozygous expression of over 20 different mutations in the SP-C gene in humans is associated with chronic interstitial lung disease (ILD) and by the demonstration of structural homology between the aggregation-prone proSP-C COOH terminus and a protein associated with familial Alzheimer-like dementia (termed BRICHOS). The overall goal of this project is to further understand the molecular mechanisms underlying the consequences of BRICHOS mutant SP-C expression as both an etiology for and a model of the epithelial dysfunction associated with the pathophysiology of interstitial lung disease. We hypothesize that mutations in the SP-C gene induce the development of aberrant protein products that adopt non-native conformations that lead to aggregation and production of a toxic gain of function. Alveolar epithelial cells (AEC) initially respond to aggregation-prone SP-C BRICHOS protein by activating the unfolded protein response (UPR) aimed at correcting misfolding. Failure of the UPR to effect refolding results in activation of cellular disposal programs including ER- Associated Degradation (ERAD) and macroautophagy to augment mutant protein clearance. In the face of failed disposal, prolonged UPR activation (i.e. """"""""ER Stress"""""""") results in elaboration of danger signals to effect cytokine elaboration and apoptosis which contribute to the abnormal wound healing and fibrotic remodeling seen in ILD. Our experimental approach utilizes genetic and pharmacologic techniques to dissect out molecular pathways underlying the cellular response to folding mutations in the SP-C gene associated with ILD. In vitro cellular models of mutant SP-C expresson developed in our laboratory will be combined with tools and reagents designed to interogate proteostatic pathways such as the UPR [Specific Aim 1] as well as ERAD and autophagy [Specific Aim 2] that participate in the homeostatic response used by AEC to handle abnormal protein clients. In addition, these model systems will be used to evaluate emerging therapeutic strategies shown to be effective in other proteostatic diseases [Specific Aim 3] thus offering the possibilty of rapid bench to bedside translation for the treatment of this devastating lung disease.

Public Health Relevance

Pulmonary fibrosis is a devastating interstitial lung disease (ILD) marked by unrelenting respiratory failure and death. It is increasingly recognized that lung epithelial cell dysfunction plays an important role in the pathogenesis of ILD. Over 20 different mutations in the Surfactant Protein C (SP-C) gene in humans are associated with lung fibrosis. Since SP-C is synthesized by alveolar type 2 cells, SP- C mutations can be used as a model system to understand epithelial cell dysfunction in ILD pathogenesis. The overall goal of this project is to characterize molecular mechanisms regulating protein homeostasis (""""""""proteostasis"""""""") in response to mutant SP-C expression. Results funded by this project will define the role of proteostatic responses (unfolded protein response, proteasomal degradation, autophagy) used by epithelial cells for cytoprotection, how their failure contributes to ILD pathogenesis and will permit rapid assessment of new therapeutic targets for ILD treatment.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Philadelphia VA Medical Center
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