Our research focuses on light dependent signalling in the retina and brain, including visual and non-visual light detection. We are also examining novel opsin photopigments and exploring their applications to optogenetics.
The functional burden of a duplex (rod/cone) retina are the associated complexities of the daily modifications that are required in the local neural network. These are vital adaptations in the primary visual pathway, yet the mechanism and regulation of these circadian/diurnal changes in retinal function remain to be fully explored. It now appears that novel photopigments, expressed in cells other than classical photoreceptors, play an important role in driving these local retinal mechanisms. Our interest in the novel photoreceptors has been strengthened by the parallel findings of our work on human vision. Using electroretinography, we demonstrated for the first time that the human primary visual pathway itself, is regulated by the activity of an irradiance detector that utilises a novel photopigment with a peak sensitivity in the blue region of the visual spectrum, around 480nm (Hankins and Lucas, 2002). These unexpected findings have allowed us to build upon the translational links between our ongoing animal and human studies.
Now researchers have proved that melanopsin is a light-sensitive pigment, by activating the gene for it inside non-vision cells, and converting them into photoreceptorsRoxanne Khamsi - Nature News
At present, my research group is best known for our physiological work on these photoreceptors that provide important light inputs to the non-visual brain. Utilising a unique combination of molecular expression (Melyan et al., 2005), cell physiology and imaging (Sekaran et al., 2003; 2005) and whole organism studies (Hankins & Lucas, 2002; Barnard et al., 2006), research from my laboratory has made a major contribution towards the understanding of a new light sensing pathway in the eye of mammals. My group has also extended our study of novel opsin transduction pathways, by pioneering heterologous expression systems. In the course of this work we provided the first definitive evidence that human melanopsin is indeed a sensory photopigment and that it has an additional function as a photoisomerase, which is more characteristic of invertebrate pigments (Melyan et al., Nature, 2005). The immediate challenge has been for us to place this system, together with classical rods and cones, within a fully functional and retinal based context, something that we have recently advanced using genetic cell ablation (Guler et al., Neuron, 2008).
With support from the BBSRC we have been exploring the wide range of non-visual opsins expressed in the eye, brain and tissues of the zebrafish. This work has led us to revise our understanding of the extent and diversity of photodetection in this model system. The ‘functional expression’ approach for elucidating the properties of novel opsins has allowed us to extend our research on the mechanistic analysis of melanopsin and relate our findings to structural components of the protein. Remarkably, the finding that expression of this single gene was sufficient to render neurones light responsive, has significant bio-technological implications and we have a current patent relating to the use of novel opsins as photosensitizing agents for clinical and technological applications. This translational research is relevant to recent developments in retinal implant technologies. We are currently employing viral gene transfer to drive heterologous expression of melanopsin and other novel light sensitizers in mice. These projects are pioneering the use of melanopsin as a tool to render neural tissue intrinsically photosensitive for experimental and therapeutic applications.
- Wellcome Trust
- Dr Sam de Silva, Wellcome Trust Clinical Research Training Fellow
- Dr Doron Hickey, Woolf Fisher Scholar and DPhil Student
- Jessica Rogers, EPSRC D.Phil. student
- Josephine Fu, D.Phil. student