The Role of the Unfolded Protein Response in the Pathogenesis of Fuchs Endothelial Corneal Dystrophy

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Fuchs endothelial corneal dystrophy (FECD) is a common disorder of the corneal endothelium leading to pain and loss of vision. FECD is a leading indication for corneal transplantations due to lack of curative medical treatments and an incomplete understanding of the underlying pathophysiology. Previous experiments indicate upregulation of the unfolded protein response (UPR) in the corneal endothelium of genetically heterogeneous human FECD specimens. The UPR is a major cell stress pathway activated in response to accumulation of misfolded proteins within the endoplasmic reticulum (ER). In the case of unresolved ER stress, it may eventually initiate apoptosis. Familial FECD has been associated with mutations in the alpha 2 collagen VIII (COL8A2) gene. A transgenic mouse model containing the human FECD COL8A2 Q455K mutation is available at the host institution. The recently conducted characterization of its corneal phenotype showed a striking similarity to the human FECD disease pattern. This mouse model provides the unique opportunity to specifically study the cellular pathophysiology of FECD in a genetically defined, in vivo system. The overall hypothesis of the proposal presented here is that corneal endothelial cell expression of the COL8A2 Q455K FECD mutation activates the UPR, resulting in endothelial apoptosis induction. To test this hypothesis the mRNA and protein levels of UPR associated genes will be assessed in COL8A2 Q455K mutant mice at different ages. Furthermore, it will be investigated if cultured endothelial cells from COL8A2 FECD mutant mice have increased sensitivity to pharmacologically induced UPR activation. These proposed studies should provide a deeper understanding of the molecular mechanisms implicated in FECD and should serve as a basis for the future development of conservative therapeutic approaches.