Grimm Lab for Retinal Cell Biology, University of Zurich, Switzerland


Although many patients worldwide suffer from aquired or inherited retinal degenerations, successful therapies are still highly needed for the 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 phenotypes makes the design of treatment strategies difficult. The main reason for the lack of effective therapies, however, may be our incomplete understanding of the molecular events leading to retinal cell death and hence to the impairment of vision.

Our work focuses on the elucidation of the biochemical events and molecular signaling cascades that lead to retinal degeneration and execute cell death. The goal is to understand the pathways induced by the diverse stimuli and to develop gene therapy and neuroprotection based strategies that may ultimately lead to the rescue of vision in patients.

Our General Research Areas

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Hypoxia and vision
Retinal cells and especially photoreceptors have a high demand of energy. Photoreceptor function relies on complex metabolic pathways involving several retinal cells and the RPE. Oxygen for photoreceptors is delivered through the capillaries in the choroid. As the eye ages, delivery of O2 may be hampered leading to mild but chronic hypoxia in RPE cells and photoreceptors. This may influence metabolism, energy production and ultimately cell survival. Our work focuses on the molecular consequences of reduced oxygen availability for photoreceptor cells and the development of treatment strategies to target the major hypoxia-inducible transcription factors in rods, cones and RPE.

Signaling in the injured retina
Photoreceptor injury or stress induces an elaborative intercellular signaling cascade that activates a neuroprotective response in Müller glia cells. At the center of this response is leukemia inhibitory factor (LIF), which is produced by a subset of Müller cells in the presence of damaged photoreceptor cells. The level of Lif expression is not only controlled by transcription but also by RNA stability. This post-transcriptional mechanism is important to control LIF levels allowing increased LIF production specifically in times of need. We investigate LIF as a survival factor and aim at stimulating its expression by pharmacological and gene therapeutic approaches specifically in the degenerating retina. We are also interested in the signaling cascades controlled by LIF and the communication between retinal cells in general.

Cones and cell death
Cones are most important for human daylight vision. They are concentrated in the macular region and needed for high acuity vision. Since only 3-5 % of all photoreceptors are cones, their metabolism, function and specific cell death mechanisms are difficult to analyze. We modified a transgenic mouse that develops a retina where all photoreceptors are cones by the introduction of a second mutation. This double mutant mouse has an all-cone retina that is functional and nicely layered. We use this model to investigate cell death mechanisms in cones and the cone response to reduced oxygen levels.

RPE and lipid metabolism
The retinal pigment epithelium is essential for photoreceptor function and survival. Among other tasks, the RPE phagocytes photoreceptor outer segment tips and disposes or recycles lipids from the internalized photoreceptor disc membranes. Evidence suggests that disturbance of this metabolic RPE function may contribute to the development of age related macular degeneration (AMD), a highly prevalent disease that affects up to 20-25% of people above the age of 75. We specifically focus on the function of ABCA1, a prominent lipid transporter in the RPE that has been connected to AMD by genetic studies. We aim at defining the potential role of ABCA1 in the development of retinal disease and at establishing therapies that may increase ABCA1 activity to prevent retinal pathologies.

The Lab of Retinal Cell Biology belongs to the Dept. of Ophthalmology, University Eye Hospital Zurich.
Head of Department: Prof. Dr. Dr. Daniel Barthelmes