Yingbin Fu
Assistant Professor of Ophthalmology and Neurobiology and Anatomy
Director of Model Development, Moran Center for Translational Medicine
Ph.D. Michigan State University
Research
Our daylight and color vision are mediated by cone photoreceptors. For quite some time, scientists do not understand why certain cone photoreceptors are more susceptible to degeneration than others in both animal models and human patients when 11-cis-retinal is lacking. We recently discovered that the short-wavelength (SW) opsins are more prone to aggregation than the medium- and long-wavelength (MW/LW) opsins in the absence of 11-cis-retinal2. The accumulation of SW opsin triggers endoplasmic reticulum (ER) stress. Our analysis suggests that this mechanism applies to all vertebrates. The first objective of the Fu lab is to determine the mechanism by which 11-cis-retinal deprivation causes SW-opsin but not MM/LW-opsin aggregation. Why are the SW (or blue) opsins so special? What are the physiological implications? How do aggregated opsins lead to rapid photoreceptor degeneration? Inefficient clearance of misfolded and misassembled proteins from the ER leads to ER stress, which has been implicated in the pathogenesis of several major diseases, e.g. diabetes, inflammation, and neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease. Our research has implications not only to retinal degeneration but also to degenerative diseases in other tissues.
Recently, photoreceptors have increasingly become an attractive model for studying neuronal cell biology (e.g. intracellular trafficking, assembly and targeting of protein complexes) due to their highly polarized structure and enormous biosynthesis requirement. However, little is known about the assembly and trafficking of photoreceptor proteins. The second objective is to understand the mechanisms governing the assembly/trafficking of key photoreceptor proteins and its role in photoreceptor survival.
The third objective is to perform functional characterization on genetic variants that are associated with age-related macular degeneration (AMD), which is among the most common causes of blindness, particularly irreversible blindness, in the world. We are witnessing a new era by researchers in identifying genetic variants associated with many complex diseases. It is more important than ever to validate the role of these variants and to uncover the underlying pathophysilogical mechanism with functional approach in this post-genomic era. We are taking advantage of the genetic power of the mouse model for this study. In fact, we have generated several exciting AMD models (see Figure) and are in the process of characterizing them. We are working actively toward the goal of developing innovative treatment strategies for these horrible blinding diseases. This is a good opportunity for students to get involved in both basic (regarding the AMD causing mechanism) and translational (designing new therapeutic treatment) research.
Students are expected to learn a variety of techniques in modern neuroscience research including genetics, electrophysiology, biochemistry, cell biology, advanced in vivo and in vitro imaging, and animal behavior.
References
- Zhang T, Baehr W, Fu Y (2012) Chemical chaperone TUDCA preserves cone photoreceptors in a mouse model of Leber congenital amaurosis. Invest Ophthalmol Vis Sci, in press
- Jones A, Kumar S, Zhang N, Tong Z, Yang J-H, Watt C, Anderson J, Fnu A, Fillerup H, Mccloskey M, Luo L, Yang Z, Ambati B, Marc R, Oka C, Zhang K, and Fu Y (2011) Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci U S A, 108, 14578-14583
- Zhang T, Zhang N, Baehr W, and Fu Y (2011) Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis. Proc Natl Acad Sci U S A, 108 (21):8879-8884
- Fu Y (2010) Phototransduction: Phototransduction in Rods. In Encyclopedia of the Eye, 1st Edition, Volume 3, pp. 397-402. Edited by Dartt D, Besharse J, Dana R. Academic Press. Elsevier Ltd
- Yang Z, Tong Z, Chen Y, Zeng J, Sun X, Zhao C, Davey L, Wang K, Chen H, London N, Muramatsu D, Salasar F, Kasuga D, Wang X, Dixie M, Zhao P, Yang R, Gibbs D, Lu F, Liu X, Li Y, Li B, Li C, Li Y, Campochiaro B, Constantine R, Zack D, Campochiaro P, Fu Y, Li D, Katsanis N, and Zhang K (2010). Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet 6, e1000836. doi:10.1371/journal.pgen.1000836
- Fu Y (2010) Phototransduction in Rods and Cones. Webvision: The Organization of the Retina and Visual System. Edited by Kolb H, Fernandez E, Nelson R. Bookshelf, U.S. National Library of Medicine, National Institutes of Health
- Fu Y, Kefalov V, Luo DG, Xie T, and Yau KW (2008) Quantal noise from human red cone pigment. Nature Neuroscience. 11: 565-571
- Fu Y and Yau KW (2007) Phototransduction in mouse rods and cones. Pflugers Arch. - Eur J of Physiol. 454:805-819
- Fu Y, Zhong H, Wang MH, Luo DG, Liao HW, Maeda H, Hattar S, Frishman LJ, and Yau KW (2005) Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin. Proc Natl Acad Sci U S A 102(29):10339-10244
- Fu Y, Liao HW, Do MT, Yau KW (2005) Non-image-forming ocular photoreception in vertebrates. Curr Opin Neurobiol. 15(4):415-22
- Kefalov V*, Fu Y*, Marsh-Armstrong N, and Yau KW (2003) Role of visual pigment properties in rod and cone phototransduction. Nature. 425:526-531
*Equal contribution co-first authors.
Updated 4/13/2012
