Abnormal development of the anterior segment in humans (anterior segment dysgenesis;ASD) leads to structural anomalies and is associated with an increased risk of glaucoma and corneal opacity. Mutations or changes in the copy number of human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma, and other extraocular anomalies. We have recently shown that ARS is also associated with corneal neovascularization, a sight- threatening condition caused by pathological angiogenesis. The long-term goal of our lab is to understand the fundamental mechanisms that regulate corneal vessel growth and anterior-segment development. The objective of this renewal application is to study the role of the transcription factors Foxc1 and Foxc2 in anterior segment development, in both developmental and pathological corneal neovascularization, and in corneal conjuctivalization. We have recently shown that inactivation of Foxc1 in the NC-lineage cells of mice leads to anterior-segment defects that are analogous to those in patients with ARS-related ASD and similar to those in conventional Foxc1 mutant embryos, including corneal neovascularization accompanied by aberrant formation of extracellular matrix in the corneal stroma. We have also completed preliminary experiments suggesting (1) that an NC-specific mutation in a closely related gene, Foxc2, leads to ectopic neovascularization in the cornea as well as impaired ocular epithelial cell identity and corneal conjunctivalization;(2) that compound, NC- specific Foxc1;Foxc2 mutants have more severe eye defects, including complete absence of the cornea, and (3) that the severity of the ocular defects is gene-dose dependent. Thus, Our central hypothesis is that Foxc1 and Foxc2 are required for eye development and corneal avascularity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine whether Foxc1 and Foxc2 are required in NC-lineage cells for early eye development;2) Elucidate whether Foxc1 and Foxc2 are essential for maintaining corneal avascularity during development and in adult animals;and 3) Define the mechanisms by which Foxc1 and Foxc2 participate in corneal neovascularization and in the establishment and maintenance of epithelial-cell identity. The approach is innovative, because the proposal comprises innovative concepts and approaches to understanding how the development of congenital eye disorders and pathological corneal neovascularization are regulated by the expression of Foxc1 and Foxc2 in cells from a variety of lineages. In summary, the proposed research is significant, because the completion of our proposed research will contribute significantly to the fields of both medicine and molecular bioscience. We expect our findings to have an important positive impact on patient care, because knowledge of these fundamental mechanisms of ocular development and corneal maintenance will likely to lead to new therapeutic strategies for the prevention and treatment of ocular disorders.
The proposed research is relevant to public health because inherited disorders of the anterior segment of the eye are common in humans, but their causes and underlying developmental mechanisms are poorly understood. The proposed studies will also significantly contribute to a better understanding of establishing and maintaining corneal avascularity and epithelial cell identity and will gain insight into the cellular and molecular bass of related human ocular diseases. Thus, the proposal is relevant to the part of NIH's mission that leads to the development of new therapeutic strategies for the prevention and treatment of ocular disorders.
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