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Prof. Dr. Christian Grimm

 

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Lab of Retinal Cell Biology
Dept Ophthalmology
University of Zurich

Wagistrasse 14
8952 Schlieren

Tel. +41 44 556 3001

cgrimm@opht.uzh.ch

Main Goals, Keywords

Molecular, biochemical and morphological analysis of photoreceptor apoptosis in induced and inherited models of retinal degeneration. Neuroprotection to prevent neurodegeneration in order to preserve vision.

Keywords: Apoptosis, photoreceptor degeneration, neuroprotection, gene expression, light-damage, Rpe65, hypoxia, erythropoietin, HIF-1, cytoskeleton, small GTPases, cytokines, Jak/STAT, leukemia inhibitory factor

Group Members

1 professor, 2 postdoctoral fellows, 5 PhD students, 2 master students, 3 technicians, 1 trainee

General Research Goals

Although many patients worldwide suffer from inherited retinal degenerations, there are currently no therapies for the successful treatment of blinding diseases like age related macular degeneration (AMD) or Retinitis Pigmentosa (RP). The diversity of the stimuli (endogenous and exogenous) and the heterogeneity of the phenotypes makes it difficult to design treatments for patients. The main reason for the lack of effective therapies, however, may be the incomplete understanding of the molecular events leading to retinal cell death and hence to the impairment of vision.

Thus, our work focuses on the elucidation of the biochemical events and molecular signaling cascades during retinal degenerations. The goal is to understand the pathways induced by the diverse stimuli in order to develop neuroprotective strategies which may ultimately lead to the rescue of vision in patients. Neuroprotection has some main advantages over alternative approaches: 1st) neuroprotection is mostly mutation independent. A single neuroprotective treatment may thus be beneficial to a large and diverse group of patients. 2nd) many patients seek treatment rather late during the disease. At this stage, a fast and effective neuroprotective treatment may save remaining cone cells. 3rd) the neuroprotective approach utilizes the cells and synaptic connections already established during retinal development. There is no need for the incorporation of new cells, genes, viruses or artificial light sensitive devices. 4th) Neuroprotection may be more economical and therefore better affordable for the individual patient and the health system as a whole.

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General research questions

1. Why do photoreceptors degenerate?

To understand retinal disease mechanisms and to develop therapeutic strategies, it is mandatory to understand retinal physiology on a systemic and on a molecular level. Endogenous and exogenous stimuli need to be defined which causes the switch from physiology to pathophysiology and thus to retinal degeneration.

2. How is cell death induced and executed?

Apart from the definition the stimuli inducing retinal degeneration, the investigation of the molecular responses and signaling cascades is of essential importance not only to identify the mechanisms of cell death execution but especially also to learn about endogenous rescue mechanisms activated to protect visual cells.

3. How are dead cells cleared?

Degeneration of retinal cells generates cellular debris which needs to be removed from the retina to avoid further damage. Phagocytosis is the central process responsible for the clearance process. Cells of the retinal pigment epithelium as well as resident and invading microglias/macrophages are the main phagocytes in the retina. Inflammatory processes may be involved in the recruitment of phagocytic cells. Controlled manipulation of these processes may reduce retinal damage and may be beneficial for diseases like AMD.

4. How can cell death be inhibited?

Recognition of the above mechanisms is required for the development of efficient strategies to reduce retinal degeneration and to prolong the period of useful vision for patients. Such strategies may be based on the controlled stimulation of endogenous and thus ‘natural’ rescue mechanism or on the interference with death mechanisms by the application of exogenous compounds. It is our goal to translate the acquired knowledge into clinical trials and, finally, into clinical applications.

Current research questions

The development of successful neuroprotective strategies needs a detailed knowledge of the molecular events during retinal degeneration. We currently focus on the investigation of the following signaling pathways in the retina.

  1. The JAK/STAT signaling pathway with focus on leukemia inhibitory factor (LIF) and signal transducer and activator of transcription 3 (STAT3).
  2. Communication between photoreceptor cells and Muller glia cells is important to activate an endogenous defense pathway in a degenerating retina. This defense pathway involves extensive signaling and the production of fibroblast growth factor 2 (FGF2)
  3. The molecular response to hypoxic preconditioning (neuroprotective treatment). Special focus is given to locally produced erythropoietin (EPO), the Epo receptor, hypoxia inducible factors (HIFs), von Hippel Lindau protein.
  4. Elucidation of the molecular mechanisms leading to age-related retinal degeneration in conditions of chronic hypoxia. Development of a gene therapy approach to preserve vision in age-related blinding disease.
  5. Analysis of cone cell death. We generated a double-mutant mouse (Nrl–/–;Rpe65R91W) with a functional and morphologically ‘normal’ all-cone retina. Using treatment with MNU or exposure to high levels of blue light, we induce cone degeneration in this mouse and study the relevant molecular mechanisms. Triple (Nrl–/–;Rpe65R91W;cpfl/cpfl) and quadruple (Nrl–/–;Rpe65R91W;cpfl/cpfl;rd10/rd10) mutant mice have generated to study inherited retinal degeneration.

Techniques and Equipment

Morphological analysis of retinal tissues by light and electron microscopy; Analysis of apoptosis by morphological, immunohistochemical (TUNEL assay) and biochemical methods; Analysis of gene expression by real-time PCR, laser capture microdissection, Western blotting and immunofluorescence; spectrophotometric analysis of rhodopsin; Cell cultures; Measurement of retinal function (ERG) and visual function (OMR).

Selected Publications

Selected Lectures, Seminars or Colloquia

BIO422 Molecular and Cellular Neurobiology; BIO402 Systems Neurobiology; BIO417 Scientific Writing and Publishing; BIO431 Advanced Physiology; V-Nr 745 Genetik, Entwicklung und Erkrankung des Auges

Funding

Swiss National Science Foundation (SNF); EU; Various Foundations; ZIHP collaborative project

URL

http://home.ggaweb.ch/LabForRetinalCellBiology

 

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© 2014 ETH Zurich | Imprint | Disclaimer | 4 December 2013
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