Dr. Chan’s research focuses on understanding the role of extracellular matrix proteolysis in normal and pathological corneal repair. Dr. Chan’s research addresses the importance of proteolysis by matrix metalloproteinases (MMPs) in modulating various aspects of the repair process following corneal injury including inflammation, neovascularization, and fibrosis. Mouse models of corneal injury and real-time imaging of cells in corneas in live mice are used. These studies will hopefully lead to the identification of novel therapeutic targets.
M. Chan, J. Li, A. Bertrand, J. Lin, I. Maltseva, S. Rosen, Z. Werb
Corneal opacification affects millions of people and is the second leading cause of blindness in the world. Corneal injury is a major cause and can occur by a variety of mechanisms including infectious and noninfectious ulcers, incisional and laser surgery, and trauma. Regardless of the type of injury, a common set of cell-extracellular matrix (ECM) interactions mediated by growth factors, cytokines, and angiogenic factors become activated in the repair process. This normal response to injury can lead to pathologic results when corneal fibrosis and angiogenesis occur. Clinically, this can result in severe corneal opacification with vision loss and corneal transplantation may be the only option to restore functional vision.
Matrix metalloproteinases are a family of extracellular proteinases and represent the most prominent group of proteinases associated with tissue repair. These enzymes become activated upon tissue injury and affect various aspects of the repair process including turnover of the ECM, angiogenesis, signaling events, and immune cell infiltration. Previous studies have shown that the expression of several matrix metalloproteinases (MMPs), including MMP-8 and MMP-12, are up-regulated in the cornea after injury implicating their roles in corneal repair. These enzymes are produced by epithelial, stromal and inflammatory cells and their roles in corneal repair have not been well-studied. Using a genetic approach, we are examining how the extracellular degradative enzymes, MMP-8 and MMP-12, contribute to the corneal epithelial and stromal repair processes. Our results suggest that these enzymes regulate the inflammatory and angiogenic responses to corneal injury. These findings are significant because corneal inflammation and angiogenesis are key determinants of the amount of scarring that will occur after injury. Therefore, these results improve our understanding of the role of extracellular enzymes in regulating molecular processes that may affect corneal fibrosis and suggest them as potential therapeutic targets for modulating corneal repair.
M. Chan, J. Lin, B. Jeng
Corneal disease can result from abnormal gene regulation and expression which has led to several genetic studies to help clarify the underlying molecular processes involved in the pathophysiology of corneal disease. While corneal genetics has given some insight into corneal disease processes, the role of epigenetic modifications in corneal disease not been characterized. Epigenetic modifications are heritable changes in gene expression that are not accompanied by changes in DNA sequence and result in alterations in gene expression. The goal of the project is to use a global DNA methylation assay to identify candidate genes that become abnormally methylated in corneal diseases and to assess the effects of reversing DNA methylation.
M. Chan, J. Li, A. Bertrand, and Z. Werb
After tissue injury, there are many dynamic cellular changes within the extracellular matrix. We are interested in the studying the behavior of cells within their microenvironment following injury. The recent development of time-lapse video microscopy has allowed for the direct visualization of these cellular dynamics in vivo and in real time. We have developed an imaging platform that has combined long-term mouse anesthesia with fluorescent, real-time microscopy so that we are able to visualize inflammatory cell dynamics in the wounded cornea of a living mouse.