Signal Transduction Mechanisms in Ocular Albinism Patients with X-linked ocular albinism type 1 display decreased pigmentation of ocular tissues and suffer a characteristic series of traits that includes poor visual acuity, nystagmus, strabismus, reduced stereopsis, and photophobia. At an anatomic-cellular level, these deficits correlate with foveal hypoplasia, fewer rod photoreceptors, misrouting of the optic nerve, and the abnormal development of macromelanosomes in the retinal pigment epithelium. At a molecular level the phenotype is due to mutations in the recently cloned ocular albinism type 1 gene (OA1). Expressed by melanosomes within the retinal pigment epithelium, OA1 amino acid sequence analysis and binding studies suggest it is a seven-transmembrane G-protein coupled receptor. The prevailing hypothesis is that either a sorting or signaling defect in OA1 ultimately accounts for the albinism phenotype. However, important controversies concerning the mechanism by which a mutation in OA1 leads to disease remain.
The specific aims of this proposal are to study the OA1/G-protein interaction in vitro and in vivo, to identify the OA1 sequence motif for melanosome sorting, and to identify potential melanocyte ligands for OA1. The methods will involve site-directed mutagenesis, phenotypic analysis of transfected cells and transgenic mice, and an orphan receptor strategy that applies biochemically purified ligands from likely tissue sources over an engineered OA1 ligand-sensor cell in a high-throughput system. Together, these studies will address whether a signaling defect or a protein sorting error accounts for the OA1 phenotype, how OA1 is targeted to melanosomes, and what is the OA1 ligand. Answers to such questions will advance our understanding of the molecular mechanisms involved in visual system development, signal transduction, and protein sorting. They may also suggest novel therapeutic strategies for treating patients suffering from this and other retinal pigment epithelium based visual impairments. Having recently completed my MD.-Ph.D. in the U.C. Irvine M.S.T.P., will conduct this research as part of my training in the EyeSTAR (Specialty Training in Advanced Research) program at the Jules Stein Eye Institute. This program integrates an Ophthalmology clinical residency and postdoctoral basic science research training with the expressed goal of developing clinician-scientist leaders in ophthalmology. Under the mentorship of Dr. Debora Farber, I hope to launch an academic career and establish a research laboratory aimed at understanding and treating retinal disease.
| Tozer, Kevin; Roller, A Brock; Chong, Lawrence P et al. (2013) Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents. Ophthalmology 120:2029-34 |
