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Molecular Biology & Genetics; Neuroscience, Institute of Genetic Medicine (IGM)
600 N. Wolfe Street
809 Maumenee Bldg.
Baltimore MD 21287
Molecular approaches to the study of retinal development and function
My laboratory uses molecular biology approaches in an effort to better understand retinal function and pathology, and attempts to use this increased understanding to develop new approaches for the diagnosis and treatment of retinal disease (age-related macular degeneration, retinitis pigmentosa, and glaucoma). We are particularly interested in defining the mechanisms regulating photoreceptor and ganglion cell gene expression, determining how gene expression changes in disease, and identifying and characterizing novel retinal genes that are important for retinal function and disease. Amongst the ongoing research projects are the following: 1) Using a combination of transgenic mouse, cell culture, in vitro transcription, and bioinformatic approaches, we have defined a number of the cis-acting elements important in photoreceptor and RPE gene regulation. Using the yeast one-hybrid and other approaches, we have cloned several of the transcription factors that bind to these elements. One of these, CRX, turns out to regulate a number of photoreceptor-specific genes. In addition, when mutated CRX can cause retinal disease. 2) We are using custom microarrays to explore how gene expression changes with retinal development, and how expression patterns are altered in human disease and in murine models of human disease. We are also exploring the pattern and mechanisms of genes that are alternatively spliced in the retina. 3) We are screening small molecule libraries for compounds that promote RGC and photoreceptor differentiation and survival. 4) In a collaboration with Ruben Adler’s and Peter Campochiaro's labs, we are exploring the mechanisms by which neurotrophic factors retard retinal degeneration. In this study we are studying gene expression at the single cell level. 5) In collaboration with Harry Quigley's lab, we are exploring the mechanisms by which retinal ganglion cells (RGCs) die in glaucoma, and exploring if inhibition of apoptosis might provide a new "neuroprotective" strategy for the treatment of glaucoma.
Esumi, N., Kachi, S., Campochiaro, P.A., and Zack, DJ. VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family. J Biol Chem, 2007. 282(3): p. 1838-50.
Kerrison, J.B. and Zack, DJ., Neurite outgrowth in retinal ganglion cell culture. Methods Mol Biol, 2007. 356: p. 427-34.
Yu, X., Lin, J., Zack, DJ., and Qian, J., Computational analysis of tissue-specific combinatorial gene regulation: predicting interaction between transcription factors in human tissues. Nucleic Acids Res, 2006. 34(17): p. 4925-36.
Qian, J., Lin, J., and Zack, DJ., Characterization of binding sites of eukaryotic transcription factors. Genomics Proteomics Bioinformatics, 2006. 4(2): p. 67-79.
Chowers, I., Wong, R., Dentchev, T., Farkas, R.H., Iacovelli, J., Gunatilaka, T.L., Medeiros, N.E., Presley, J.B., Campochiaro, P.A., Curcio, C.A., Dunaief, J.L., and Zack, DJ., The iron carrier transferrin is upregulated in retinas from patients with age-related macular degeneration. Invest Ophthalmol Vis Sci, 2006. 47(5): p. 2135-40.
Qian, J., Esumi, N., Chen, Y., Wang, Q., Chowers, I., and Zack, DJ., Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation. Nucleic Acids Res, 2005. 33(11): p. 3479-91.
Otteson, D.C., Lai, H., Liu, Y., and Zack, DJ., Zinc-finger domains of the transcriptional repressor KLF15 bind multiple sites in rhodopsin and IRBP promoters including the CRS-1 and G-rich repressor elements. BMC Mol Biol, 2005. 6: p. 15.
Kerrison, J.B., Duh, E.J., Yu, Y., Otteson, D.C., and Zack, DJ., A system for inducible gene expression in retinal ganglion cells. Invest Ophthalmol Vis Sci, 2005. 46(8): p. 2932-9.
Wang, Q.L., Chen, S., Esumi, N., Swain, P.K., Haines, H.S., Peng, G., Melia, B.M., McIntosh, I., Heckenlively, J.R., Jacobson, S.G., Stone, E.M., Swaroop, A., and Zack, DJ., QRX, a novel homeobox gene, modulates photoreceptor gene expression. Hum Mol Genet, 2004. 13(10): p. 1025-40.
Hackam, A.S., Strom, R., Liu, D., Qian, J., Wang, C., Otteson, D., Gunatilaka, T., Farkas, R.H., Chowers, I., Kageyama, M., Leveillard, T., Sahel, J.A., Campochiaro, P.A., Parmigiani, G., and Zack, DJ., Identification of gene expression changes associated with the progression of retinal degeneration in the rd1 mouse. Invest Ophthalmol Vis Sci, 2004. 45(9): p. 2929-42.