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"Understanding and controlling mammalian photoreceptor functions in health and disease"

Busskamp, Volker. "Understanding and controlling mammalian photoreceptor functions in health and disease". 2010, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9222

Abstract

My thesis consists of two major chapters, (i) a biomedical project about reactivating non functional cone photoreceptors in a disease background and (ii) a more basic project about microRNA turnover in healthy photoreceptors. Both projects were published in 2010 and summarized as follow:
i. Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy. (Busskamp et al. Science. 2010 Jul 23;329 (5990):413-7. Epub 2010 Jun 24.)
ii. Adaptation to different levels of illumination is central to the function of the retina. Here we demonstrate that levels of the miR-183/96/182 cluster, miR-204, and miR-211 are regulated by different light levels in the mouse retina. Concentrations of these microRNAs were down-regulated during dark adaptation and up-regulated in light-adapted retinas, with rapid decay and increased transcription being responsible for the respective changes. We identified the voltage-dependent glutamate transporter Slc1a1 as one of the miR-183/96/182 targets in photoreceptor cells. We found that microRNAs in retinal neurons decay much faster than microRNAs in non-neuronal cells. The high turnover is also characteristic of microRNAs in hippocampal and cortical neurons, and neurons differentiated from ES cells in vitro. Blocking activity reduced turnover of microRNAs in neuronal cells while stimulation with glutamate accelerated it. Our results demonstrate that microRNA metabolism in neurons is higher than in most other cells types and linked to neuronal activity. (Krol et al. Cell. 2010 May 14;141(4):618-31.)
Advisors:Gasser, Susan
Committee Members:Roska, Botond and Bamberg, Ernst
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
Item Type:Thesis
Thesis no:9222
Bibsysno:Link to catalogue
Number of Pages:124 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:21 Jan 2011 11:32

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