The overall goal of this work is to define the mechanisms that lead to the development of tissues in the anterior segment of the eye and the hyaloid vasculature. Persistent Hyperplastic Primary Vitreous (PHPV, or PFV) is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress, and generates secondary glaucoma, cataracts, retinal detachment, and intravitreal hemorrhage. There is no clear understanding of the overlapping molecular pathways responsible for regression of the primary vitreous. Our preliminary studies indicate that targeted mutation of the Zfhx1a gene in mice causes an ocular defect similar to PHPV, and including defects of the cornea and metaplasia at the iridocorneal angle. This is surprising because it indicates that Zfhx1a is a critical step in a regulatory pathway essential for eye development. This is supported by the recent identification of Zfhx1a mutations in Posterior Polymorphous Corneal Dystrophy-3 (PPCD3) families. We propose to define the ocular developmental defects in Zfhx1a-null embryos, and identify the relevant molecular pathway(s). Our overall hypothesis for these studies is that Zfhx1a regulates a novel critical step in BMP-mediated oculogenesis.
Specific Aim #1 will characterize the developmental defects of the eye in Zfhx1a-mutant mice. We will define the extent and timing of PHPV in Zfhx1a-null and Zfhx1a-het mice, and characterize associated defects of the cornea and iris. We will define the cell type(s) within the vitreous and cornea that are involved in the ocular defects, and investigate changes in proliferation rate and apoptosis. We will use immunohistochemistry to investigate changes in expression of potential downstream genes involved in vascularization or regression.
In Specific Aim #2, we will use genetic crosses to define the relevant signaling pathways. Together, these experiments will define the critical role for Zfhx1a in development of the anterior eye, and provide a foundation and genetic tools for future studies on how the Zfhx1a pathway is integrated with other signaling pathways. The long-term goal of this work is to define signaling pathways and cytokine-based therapies for treatment of congenital eye defects, including PHPV and PPCD-3. The overall long term goal of this research is to define major molecular signaling pathways required for regression of the fetal hyaloid vasculature and genesis of the cornea. Defining the molecular mechanisms that contribute to ocular diseases in humans is a significant goal. Identification of multiple signaling pathways that direct the regression of hyaloid vasculature should allow a therapeutic approach to the treatment of Persistent Hyperplastic Primary Vitreous (PHPV) by intraocular injection. PHPV is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress. A number of clinical findings are frequently associated with PHPV, including microphthalmos, glaucoma, shallowing of the anterior chamber, corneal opacity, congenital cataract, coloboma, and retinal degeneration (11-13). Even mild cases are associated with amblyopia. A very early therapeutic treatment is needed to prevent later secondary defects. This directly relates to the National Eye Institute program's goal to investigate the development of the visual system. ? ? ?
