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4 YEAR PhD IN NEUROSCIENCE
Rachael A Pearson
Institute of Ophthalmology
Stem Cell Therapy and Retinal Degeneration
Inherited retinal disease and age-related macular degeneration are associated with the loss of photoreceptors and, subsequently, visual impairment and blindness. We have recently established a proof-of-principle for both rod (MacLaren & Pearson et al., Nature, 2006) and cone (Lakowski & Baron et al., Hum. Mol. Gen., 2010) photoreceptor cell replacement therapy in the eye. We were able to demonstrate that transplantation of cells at a specific stage in development results in their integration and subsequent differentiation into rod photoreceptors. Importantly, these cells form synaptic connections and improve vision in models of retinal degeneration (Pearson et al., in preparation). Together with my mentor, Professor Robin Ali (IOO), and our collaborator Dr Jane Sowden (ICH), my group is now working to develop of these findings for the provision of cell-based mechanisms for retinal repair and regeneration.
Improving integration: the degree of visual function we can hope to restore by photoreceptor transplantation will depend critically upon the numbers of cells we can get to correctly integrate within a recipient retina. To do so, we need to understand the mechanisms by which donor cells migrate and integrate into the recipient retina and to determine the factors that may impede or enhance cell integration.
Functional analysis of retinal repair: For cell transplantation to have importance in the clinic, it is essential to determine its impact on visual function and acuity. We are fortunate to be able to apply a wide array of techniques both cellular and system based, including single cell suction electrode recordings, electroretinogram recordings, pupillometry, visually-evoked potential recordings and behavioural testing. Generation of photoreceptor precursors from stem cells in vitro: We are investigating the in vitro potential to differentiate neuronal cells from endogenous stem/progenitor cell populations. We have developed protocols for the expansion and maintenance of these cells and are now combining these techniques with gene therapy approaches in order to drive these cells towards a state equivalent to the post-mitotic photoreceptor precursor cell, and assess whether or not this can produce appropriate cells for transplantation. One intriguing area of research is the reactivation of endogenous stem cells populations. We are interested in examining the role of purinergic signalling in controlling retina stem cell proliferation and whether this mechanism has become restricted through evolution.
Understanding photoreceptor fate: We have observed that the recipient environment plays a significant role in the fate acquired by donor cells. We wish to determine the mechanisms behind this and how such mechanisms may differ with respect to normal photoreceptor development.
AVAILABLE PROJECTS
Purinergic signalling as an evolutionarily restricted signalling mechanism in the control of retinal stem cell proliferation.
Plasticity of photoreceptor fate.
Rescue of cone degeneration by transplantation.
SELECTED PUBLICATIONS
Pearson RA*, West EL*, Barker SE, Luhmann UFO, MacLaren RE, Barber AC, Duran Y, Smith AJ, Sowden JC, Ali RR. (2010) Long term survival of photoreceptors transplanted into the adult neural retina requires immune modulation Stem Cells. (In Press)
Lakowski J, Baron M, Bainbridge J, Barber A, Pearson RA, Ali RR, Sowden JC. (2010) Generation of New Cone and Rod Photoreceptors in models of Lebers congenital amaurosis by Transplantation of Crx-Positive Precursor Cells. Hum. Mol. Gen. (In Press)
Pearson RA, Barber A, West, EL, Duran Y, MacLaren RE, Bainbridge J, Sowden J.C, Ali RR (2010) Genetic and molecular manipulations of the outer limiting membrane lead to robust integration of transplanted photoreceptor precursors into the adult eye. Cell Transplantation. 19(4):487-503.
Pearson RA*, MacLaren RE*, MacNeil A, Douglas RH, Salt TE, Akimoto M, Swaroop A, Sowden JC, Ali RR (2006). Retinal repair by transplantation of photoreceptor precursors. Nature 444(7116):203-7.
Pearson RA, Dale N, Llaudet E, Mobbs P (2005) ATP released via gap junction hemichannels from the pigment epithelium regulates neural retinal progenitor proliferation. Neuron. 46. 731-744
More: http://www.ucl.ac.uk/ioo/pdf/PI/Dr%20Rachael%20Pearson.pdf
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