Congenital eye anomalies are an important cause of childhood blindness. Malformations of the cornea, iris, and iridocorneal angle result from anterior segment dysgenesis and include Axenfeld-Rieger Syndrome (ARS) and primary congenital glaucoma (PCG). In these diseases, visual impairment is often due to severe glaucoma that can be refractory to surgical treatment. These congenital anomalies are due to disruption of the neural crest, a transient population of stem cells that gives rise to the corneal stroma and endothelium, iris stroma, trabecular meshwork, and sclera. This work aims to understand the biology of neural crest migration, proliferation, survival, and differentiation in te formation of the eye. My goal is to gain insight into the pathogenesis of these diseases in order to develop novel therapeutic approaches that could prevent blindness in these children. The overarching hypothesis that guides this work is that disruptions in ocular neural crest migration, proliferation, survival, and differentiation lead to anterior segment malformations. I propose to study the biology of the ocular neural crest in a zebrafish model as a means to identify and experimentally test developmental pathways involved in the formation of the anterior segment. In addition, this project will investigate the molecular mechanisms by which genes associated with congenital eye anomalies (ie. PITX2 in ARS and CYP1B1 in PCG) regulate the ocular neural crest.
Three specific aims are proposed to test the central hypothesis: 1) Determine the role of the essential morphogen retinoic acid in ocular neural crest migration, proliferation, survival, and differentiation, 2) Determine the role of genes associated with congenital eye diseases (PITX2 and CYP1B1) in ocular neural crest migration, proliferation, survival, and differentiation, 3) Identify additional genes expressed in the neural crest that are required for anterior segment formation. As an academic pediatric ophthalmologist, I have clinical and research interests in ocular anomalies, specifically malformations of the anterior segment. As a faculty member at the University of Michigan, my clinical specialty will be treating children with congenital eye anomalies and my research program will study the signaling networks that regulate ocular morphogenesis. The Department of Ophthalmology and Visual Sciences has a world-class faculty and facilities. In particular, I will benefit from thoughtful, "hands-on" mentoring by experienced scientists and clinicians who are deeply committed to my success.
Congenital eye abnormalities such as Axenfeld-Rieger Syndrome and primary congenital glaucoma are important causes of blindness in children and young adults. Hence, these diseases represent important public health concerns due to the need for life-long vision services, loss of productivity, and reduced quality of life. This project uses zebrafish to study the biology of ocular neural crest-derived tissues in order to better understand the genetic basis for eye anomalies and help develop new treatment approaches.