Goal of our research on Fuchs Endothelial Corneal Dystrophy
The laboratory of Ula V. Jurkunas, MD, was the first to derive a telomerase immortalized corneal endothelial cell line which provides an important new tool for the in vitro study of corneal endothelial cell biology. We are currently funded by an RO1 grant from the NEI/NIH for the proposed studies and also have filed an international patent application for the treatment of corneal endothelial disorders. The research proposal specifically seeks to understand why there is greater female prevalence of FECD by studying reactive estrogen metabolites, mitochondrial biogenesis, and DNA damage response pathways in Fuchs dystrophy. Specifically, the laboratory has undertaken studies to determine how oxidative stress causes molecular and cellular damage in the susceptible FECD endothelium. These studies are significant because understanding the key regulators of antioxidant defense and oxidative stress-induced cellular damage may facilitate development of pharmacotherapeutic treatment for FECD patients.
In my laboratory, we use both in vitro and in vivo models to elucidate the molecular mechanisms that regulate the pathogenesis of FECD. Most importantly, these studies are corroborated with observations from human specimens that are obtained from Endothelial Keratoplasty of FECD cases performed by multiple corneal surgeons within the Boston metro area as well as from other states within the U.S. who collaborate with us on our FECD study. We also collaborate with the Wiggs and Vandenberghe laboratories (Mass Eye and Ear), in order to understand how the underlying genetic causes of FECD lead to the mitochondrial dysfunction and cell death. Our current research focuses on the following areas:
- The role of Endothelial-Mesenchymal transition (EnMT) in triggering oxidative stress induced pathology
- Effect of antioxidant-oxidant imbalance on the function of corneal endothelial function
- Role of reactive estrogen metabolites in initiating an estrogen genotoxic pathway in FECD
- Effect of oxidative stress induced mitochondrial DNA damage
- Investigate the role of DNA Damage Response (DDR) pathway regulating mitochondrial and nuclear DNA repair system under oxidative stress
Limbal Stem Cell Deficiency
The second main area of our research is the development of autologous cultivated epithelial stem cell constructs for patients suffering from corneal blindness due to limbal stem cell deficiency. We have been collaborating with the Center for Human Cell Therapy Boston, a unique resource that functions across different departments and affiliated institutions of Harvard Medical School. Concurrently, we were awarded the Production Assistance for Cellular Therapies (PACT) grant from National Heart/Lung and Blood Program of NIH to aid in the translational development of stem cell therapy in corneal disorders. We are in the process of filing an Investigational New Drug (IND) application to FDA for performing the Phase I/II study to treat corneal blindness with the stem cells.
- Screening and Characterization of Drugs That Protect Corneal Endothelial Cells Against Unfolded Protein Response and Oxidative Stress
- Limbal Stromal Tissue Specific Stem Cells and Their Differentiation Potential to Corneal Epithelial Cells
- Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy
- UV-A Irradiation Activates Nrf2-Regulated Antioxidant Defense and Induces p53/Caspase3-Dependent Apoptosis in Corneal Endothelial Cells
- Existence of Neural Crest-Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium
- Validity and Reliability of a Novel Ocular Pain Assessment Survey (OPAS) in Quantifying and Monitoring Corneal and Ocular Surface Pain