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Gene Expression Laboratory

  • Overview

    The principal research area of the Retinal Neurobiology Laboratory, under the direction of You-Wei Peng, M.D., Ph.D., is the neurobiology of vertebrate photoreceptors and the molecular mechanisms underlying retinal degeneration. One of our current projects is to study the disease mechanism of retinal degeneration in Usher syndrome. We also study the mechanism of protein translocation in photoreceptors and synaptic remodeling during photoreceptor degeneration. Our most recent results indicate that several animal models of Usher syndrome show defective protein translocation in their photoreceptors. Even moderate light can induce degeneration of their photoreceptors. In collaboration with the Gene Expression Lab, Oxford Biomedica and the Foundation Fighting Blindness (FFB), we initiated a gene therapy study. Results of this study show that subretinal delivery of EIAV-based lentiviral vectors expressing wild type MYO7A in the shaker1, a well accepted model for Usher syndrome type 1B, is able to rescue the transducin translocation phenotype and protect the retina from light-induced photoreceptor degeneration in the shaker1 mice, demonstrating that these phenotypes are caused by dysfunction of myosin VIIa. We are currently studying the mechanism of how mutations in MYO7A cause defective translocation and light-induced photoreceptor degeneration in the shaker1 mice.

    Usher Syndrome is the leading genetic disorder of combined blindness and deafness. The main clinical symptoms of the disease are retinitis pigmentosa (RP) and hearing loss. Affected individuals have a sensorineural hearing impairment at birth and later develop progressive RP (a special type of photoreceptor degeneration). Vestibular dysfunction and mental disturbances are also, in some cases, features of the syndrome. Several genes responsible for different forms of Usher syndrome have now been identified. The course and mechanism of retinal degeneration, however, remain unclear. Considering the tremendous burden imposed by the loss of both major senses and the fact that Usher syndrome is the major cause of deafness/blindness, it is important to pursue research into the causes of Usher syndrome in the hope that someday an effective therapy may be possible. Our most recent results indicate that even moderate light exposure can induce photoreceptor degeneration in several animal models of Usher syndrome. More importantly, when these animal models were reared under a moderate light (room light intensity)/dark cycle they develop severe retinal degeneration in less than 6 months. These finding demonstrate that Usher syndrome patients are thus likely vulnerable to light induced photoreceptor damage even under moderate room light.

  • Publications

    1. Peng, Y.-W. & Lam, D.M.K. (1991). The organization and development of horizontal cells in the goldfish retina, 1. The use of monoclonal antibody AT101. Visual Neurosci. 6, 357-370.
    2. Peng, Y.-W., Sharp, A.H., Snyder, S.H. & Yau, K.W. (1991). Localization of the inositol 1,4,5-trisphosphate receptor in synaptic terminals in the vertebrate retina. Neuron 6, 525-531.
    3. Peng, Y.-W. & Lam, D.M.K. (1992). The organization and development of horizontal cells in the goldfish retina, 2. Immunocytochemical studies with monoclonal antibody MH1. Visual Neurosci. 8, 231-241.
    4. Peng, Y.-W., Robishaw, J.D., Levine, M.A. & Yau, K.-W. (1992). Retinal rods and cones have distinct G protein beta and gamma subunits. Proc. Natl. Acad. Sci. USA 89, 10882-10886.
    5. Chen, T.-Y., Peng, Y.-W., Dhallan, R.S., Ahamed, B., Reed, R.R. & Yau, K.-W. (1993). A new subunit of the cyclic nucleotide-gated cation channel in retinal rods. Nature 362, 764-767.
    6. Xiang, M., Zhou, L., Peng, Y.-W., Eddy, R.L., Shows, T. B. & Nathans, J. (1993). ​Brn-3b, a POU-domain gene expressed in a subset of retinal ganglion cells. Neuron 11, 689-701.
    7. Dryja, T.P., Finn, J.T., Peng, Y.-W., McGee, T.L., Berson, E.L. & Yau, K-W. (1995). Mutations of the rod cGMP-gated channel causing autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 92, 10177-10181.
    8. Peng, Y.-W., Blackstone, C.D., Huganir, R.L. & Yau, K.-W. (1995). Distribution of glutamate receptor subtypes in vertebrate retina. Neurosci. 66, 483-497.
    9. Peng, Y.-W., Rhee, S.G., Yu, W.-P., Ho, Y.-K., Schoen, T., Chader, G.J. & Yau, K.-W. (1997). Identification of components of a phosphoinositide signaling pathway in retinal rod outer segment. Proc. Natl. Acad. Sci. USA 94, 1995-2000.
    10. Peng, Y.-W., Hao, Y., Petters, R.M. & Wong, F. (2000). Ectopic synaptogenesis in the mammalian retina caused by rod photoreceptor-specific mutations. Nature Neurosci. 3, 1121-1127.
    11. Lu, C., Peng, Y.-W., Shang, J., Pawlyk, B. S., Yu, F. & Li, T. (2001). The mammalian RdgB2 is not required for photoreceptor function and survival. Neurosci. 107, 35-41.
    12. Peng, Y.-W., Senda, T., Hao, Y., Matsuno, K. & Wong, F. (2003). Ectopic synaptogenesis during retinal degeneration in the royal college of surgeons rat. Neurosci. 119, 813-820.
    13. Shen, J., Yang, X., Dong, A., Petters, R.M., Peng, Y.-W., Fulton Wong, F. & Campochiaro, P.A. (2005). Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa. J. Cell. Physiol. 203, 457-464.
    14. Peng, Y. W. & Wong, F. (2007). Synaptic remodeling in retinal degeneration. In J. Tombran-Tink & C. J. Barnstable (Eds.), Retinal Degeneration: Biology, Diagnostics and Therapeutics. Humana Press, Totowa, NJ, pp. 269-289.
    15. Peng, Y.W., Zallocchi, M., Meehan, D.T., Delimont, D., Chang, B., Hawes, N.L., Wang, W. & Cosgrove, D. (2008). Progressive morphological and functional defects in retinas from alpha1 integrin-null mice. Invest. Ophthalmol. Vis. Sci. 49(10), 4647-4654. [PMCID: PMC2625300]
    16. Peng, Y.-W., Zallocchi, M., Wang, W., Delimont, D. & Cosgrove, D.E. (2011). Moderate light induced degeneration of photoreceptors with delayed transducin translocation in shaker1 mice. Invest. Ophthalmol. Vis. Sci. (In Press).