Molecular Dysregulation in Fuchs Corneal Endothelial Dystrophy

摘要

Abstract Fuchs Corneal Endothelial Dystrophy (FECD) is a blinding disease that affects millions of people (4% over the age of 40) in the U.S, for which there is no cure. Endothelial cell loss, thickening of the extra cellular matrix (ECM) or Descemet’s membrane, presence of extracellular deposits (guttae) are observed in patients with FECD. Corneal transplantation is the prevalent treatment approach, and FECD accounts for the majority of corneal transplantations in the world. On a cellular level, increased oxidative stress, expression of endothelial to mesenchymal transition (EMT) genes, and an accumulation of unfolded proteins are present in FECD. In the current proposal, I plan to identify and characterize the reasons for a) the accumulation of unfolded proteins and other debris in the cells, and b) elevated EMT. Our preliminary data show that the components of two main protein clearance pathways in eukaryotes; autophagy and the ubiquitin proteasome pathway (UPP), are significantly reduced in FECD cells. In Aims 1 and 2, I plan to identify whether oxidative stress is the cause for these decreased activities, use pharmacological agents to restore functions of autophagy and UPP, and determine whether these can alleviate the disease progression. Increased integrin activity and decreased Wnt signaling was observed in FECD. Both these signaling pathways are known to regulate EMT, which implicated in FECD disease progression. In Aim 3, I plan to determine if oxidative stress is the cause for the upregulation of integrin and repression of Wnt pathways in FECD, and to assess the roles of these signal transductions on EMT. I plan to conduct Aims 1 and 2 during the K99 phase in Indiana University Bloomington. In addition to establishing my independence from my current lab, I will also take part in career development opportunities available at Indiana University Bloomington to prepare for the job market, improve science communication as well as mentoring skills. Aim 3 will be performed during the R00 phase. Successful completion of these aims will lead to the identification and characterization of molecular mechanisms that are awry in FECD, and determine whether restoration of these pathways would suffice in the amelioration of the disease progression.