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Main Goals, Keywords Molecular, biochemical and morphological analysis of photoreceptor apoptosis in an animal model of light-induced retinal degeneration and in inherited diseases.(Apoptosis, photoreceptor, gene expression, c-fos/AP-1, rhodopsin, light-damage)
Group Members 1 professor, 2 postdoctoral fellows (Ph.D.), 1 MD, 3 technicians, 2 medical doctorate students, 2 guest-scientists.
Previous and Current Research 10% of individuals over the age of 60 suffer from age related macular degeneration (AMD) that eventually leads to severe visual disturbance. Every third person in 1000 looses vision due to the inherited disease retinitis pigmentosa (RP). Both, AMD and RP are incurable to date. Both diseases have in common that the photoreceptor cells die by apoptosis. We are studying photoreceptor apoptosis in an animal model of light-induced retinal degeneration to investigate signaling and effector pathways. Using transgenic mice, we identified the protooncogene and transcription factor c-fos as an essential component for the induction of photoreceptor apoptosis by light: Kockout mice lacking a functional c-fos gene are completely protected against light induced apoptosis. However, since apoptosis can be induced by other stimuli in adult and embryonic photoreceptors in the absence of c-fos, this gene might be involved in the signaling pathway specific for induction of apoptosis by light. We are currently searching for genes that are differentially expressed by light and that are under control of the transcription factor c-Fos (AP-1).A second approach towards the understanding of light-induced photoreceptor apoptosis tries to identify the chromophore(s) that absorb enough of the damaging light to generate the signal to dye. In line with this we established a spectral dependency of light-induced apoptosis: blue light (403nm) very efficiently induces apoptosis, whereas green light (550nm) does not. We are testing whether the photopigment rhodopsin might be the chromophore for the damaging effect of blue light. Although rhodopsin is being bleached by both blue and green light with comparable quantum efficiency, rhodopsin exposed to blue light can absorb at least 500 times more photons per time than in green light. This is due to a process called photoreversal of bleaching which occurs in the living eye, as we could show.
Future Projects We will continue our quest for genes involved in the regulation of light-induced apoptosis and the investigation of the chromophore(s) for the light-damage.In collaboration with other research groups we will also establish techniques and strategies for the application of gene therapy in the mouse.
Techniques and Equipment Morphological analysis of retinal tissues by light and electron microscopy; Analysis of apoptosis by morphological, immunohistochemical (TUNEL assay) and biochemical (formation of DNA ladder) methods; Analysis of gene expression by semiquantitative RT-PCR, Western blotting and immunohistochemical staining; Analysis of differentially expressed genes by differential display and membrane array hybridizations; Analysis of protein-DNA interactions by electric mobility shift assays (EMSA); Spectrophotometrical analysis of bleaching of rhodopsin by light; Primary cultures of retinal pigment epithelial cells.
Selected Publications:
Selected Lectures, Seminars or Colloquia
Funding Swiss National Science Foundation, SUVA, Bruppacher Foundation, Grimke Foundation, Horton Stiftung, EMDO, Hartmann Müller-Stiftung, others
URL under construction
D. Farber; Jules Stein Eye Institute, UCLA, USA; M. Redmond, NEI/NIH, Bethesda, USA; E. Zrenner, University of Tübingen, Tübingen, D; M. Yanif, Institute Pasteur, Paris, F; T. Williams, Florida State University, Tallahassee, USA; C. Richter, ETH, Zürich, CH; B, Weber, Institute of Human Genetics, Würzburg, D; G. Niemeyer, Neurophysiology, Eye Clinic, University Hospital Zürich, CH. Center Grant of the German National Research Foundation on age-related maculopathy. | ||||||||
