Impairment of the UPP and choroidal neovascularization
The ubiquitin-proteasome pathway (UPP) plays critical roles in various cellular functions, including signal transduction, transcription, cell cycle and protein quality control. This project is to test a novel hypothesis that age- and stress-related impairment of the UPP in RPE is a key contributor to the pathogenesis of age-related macular degeneration (AMD) using transgenic mice to specifically impair the UPP in the retinal pigmented epithelia (RPE). Results obtained from this study will not only help understand the pathogenesis of AMD, but also potentially provide a novel animal model of AMD that could be used to screen potential therapeutic compounds for treatment or prevention of this devastating disease.
Age-related macular degeneration (AMD) is the leading cause of legal blindness in industrialized countries. Currently ~1.7 million Americans suffer from AMD. With growth in the aging population, the prevalence and toll of this disease will increase in the near future. It is predicted that ~3 million Americans will loss vision due to AMD by 2020. However, the mechanism of this disease remains elusive and current therapeutic options are limited. Elucidation of the molecular mechanisms of AMD and establishment of a physiological relevant animal model of AMD will help the development of strategies for prevention and treatment of this devastating disease. The ubiquitin-proteasome pathway (UPP) is a cellular protein degradation system which plays critical roles in various cellular functions, including signal transduction, transcription, cell cycle and removal of damaged proteins. Our recent data indicated the UPP is compromised in retinal pigment epithelium and retinas of the elderly. Oxidative insults to retinal pigment epithelial cells also lead to inactivation of the proteasome, which in healthy cells is involved in the degradation and recycling of un-needed proteins. Furthermore, oxidative inactivation or chemical inhibition of the proteasome in retinal pigment epithelial cells induces the production of signaling molecules that could trigger the development AMD-like features. The goal of this project is to investigate whether impairment of the UPP is sufficient to trigger the onset and progress AMD. Our pilot experiments show that impairment of the UPP by production of mutant ubiquitin causes choroidal neovascularization in transgenic mice, a typical feature of wet AMD. The specific aims of this project are to characterize AMD-phenotypes in the retina and retinal epithelium of transgenic mice that produce mutant ubiquitin in retinal pigment epithelium. Successful completion of this project will not only help understand the mechanisms of AMD, but also provide a novel animal model of AMD for screening potential therapeutic compounds for treatment or prevention of this devastating disease.