Molecular Mechanisms of Eye Diseases

Using the mouse as a model system, my laboratory is attempting to identify the molecular mechanisms that underlie a number of significant eye diseases, including microphthalmia, cataracts, and retinal degeneration/dysplasia. These diseases might at first appear to have little in common. However, children born with Congenital Muscular Dystrophy (also referred to as muscle-eye-brain disorders) often present with this cluster of defects, ranging widely in severity.

Very little is known about what causes these ophthalmological abnormalities. However, it has recently been discovered that genetic defects in a family of enzymes that modify the strength of laminin binding to its cellular receptors are present in these children. We are therefore investigating what cellular signaling pathways are triggered by laminin (and other extracellular matrix) binding, and whether alteration of these pathways results in eye pathology.

Focal adhesion kinase (FAK), close family member Pyk2, and integrin-linked kinase (ILK) are central players required for transducing signals from the extracellular matrix to the cytoskeleton, and are the primary focus of the research in my laboratory. Tight regulation of their activity is required for cellular migration, survival, and proliferation in multiple systems, as well as for organization of cellular basement membranes. These kinases are also signaling nodes, and may integrate signals from other adhesion and growth factor receptors. Careful analysis of the upstream and downstream signaling pathways activated by FAK and related kinases in individual cell types, may uncover new cellular mechanisms of eye development and disease as well as potentially lead to new therapeutic targets.

Current available projects in the laboratory include generation and analysis of cell-type specific conditional knockout mouse models, analysis of FAK, Pyk2 and ILK signaling redundancy, and use of gene transfer technology to try to correct eye-related developmental defects.