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Cambridge Centre for Brain Repair |
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| School of Clinical Medicine > Cambridge Centre for Brain Repair |
Keith Martin, MA DM MRCP FRCOphthUniversity Lecturer in Ophthalmology, Department of Clinical Neurosciences Honorary Consultant in Ophthalmology, Addenbrooke's Hospital GSK Clinician-Scientist Fellow Group Leader, Cambridge University Centre for Brain Repair
Interest/role: Ophthalmology E-mail address: krgm2@cam.ac.uk Biosketch Keith Martin qualified from Oxford University Clinical School in 1993 and trained in general medicine and neurology at Hamersmith Hospital and the National Hospital for Neurology & Neurosurgery in London and the John Radcliffe Hospital in Oxford . His Higher Specialist Training in Ophthalmology was undertaken at Addenbrooke's Hospital in Cambridge . He completed three years of post-doctoral research on the pathogenesis of retinal ganglion cell death glaucoma at the Wilmer Eye Institute, Johns Hopkins University , Baltimore , USA and at the Institute of Ophthalmology in London . He was awarded a Doctor of Medicine degree by Oxford University in 2004 and a GSK Clinician-Scientist Fellowship in 2005. Clinically, he specialises in the medical and surgical management of adult and paediatric glaucoma patients with a particular interest in advanced, complex and uveitic disease. Current research work is focused on the mechanisms of visual loss in glaucoma and the development of new treatment approaches.
Research interests Glaucoma Glaucoma is the commonest cause of irreversible blindness in the world. The condition involves progressive death of retinal ganglion cells in the eye resulting in irreversible visual loss. Recent evidence suggests that neuronal death in glaucoma shares mechanisms with other neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Thus, advances in our understanding of glaucoma may have implications for other brain diseases and vice versa. We now have effective treatments that can dramatically slow the progress of glaucoma by lowering eye pressure. However, as the onset and progression of glaucoma are frequently asymptomatic, this detectable and treatable disease remains the leading cause of irreversible blindness worldwide. In addition, some people with severe glaucoma continue to deteriorate even when very low eye pressure is achieved. For the large numbers of individuals already blind or severely visually impaired due to glaucoma, conventional treatment offers no chance of visual improvement. This highlights a pressing need for new therapies directed at slowing the death of RGC and replacing them once they have been lost. In addition, there are many other examples of optic nerve pathologies, including optic nerve trauma, Leber's hereditary optic neuropathy and ischaemic optic neuropathy, where no currently available treatment can improve vision once it has been lost. Thus, the clinical need for new techniques of optic nerve restoration is indisputable. Death of retinal ganglion cells (RGC) is the principal pathological finding in glaucoma, leading to progressive visual field loss and eventually to blindness. Elevated intraocular pressure (IOP) is by far the most important risk factor for the development and progression of glaucoma. IOP-lowering treatment is therefore the current mainstay of glaucoma treatment. However, some patients with glaucoma worsen and go blind despite maximal IOP reduction. The raised IOP may therefore initiate a neurodegenerative process in RGC that is not stopped by present glaucoma treatments. At present, there is no available treatment that can restore visual function once RGC have died. An important goal of our group is to understand better the mechanisms of RGC death in glaucoma, to develop methods to protect RGC thus slowing the progression of glaucomatous visual loss, and ultimately to restore vision in those blind due to the disease. We have developed a novel model of glaucoma that has proven to be very useful in the investigation of glaucoma pathogenesis. The model allows RGC death to be studied both during the period of increased IOP and after IOP has fallen back to normal levels. Using this model, we have demonstrated potentially important changes in retinal glutamate transporters occuring as a specific response to elevated intraocular pressure, suggesting a new target for glaucoma therapy in the future
Current projects 1. Stem cells as a potential treatment for glaucoma We are actively investigating the ability of different types of stem cell to integrate into the glaucomatous retina. Current cells of interest include oligodendrocyte precursor cells, mesenchymal stem cells and Muller stem cells derived from the adult human retina. We have developed a novel retinal explant model which has allowed us to gain new insights into the barriers to the survival, migration and integration of transplanted cells. We are also using what is known about the control of retinal neurogenesis during development to develop methods to control the differentiation of donor cells prior to transplantation into the diseased retina. 2. Mechanisms of axonal injury in glaucoma Axonal injury appears an important trigger of axonal and cell body degeneration in glaucoma and other neurodegenerative diseases. We have recently discovered that the Wallerian degeneration slow ( WldS) mutation can delay optic nerve degeneration in a model of glaucoma. Axonal degeneration must be prevented for the optic nerve to remain functional, so in our current work we are looking for ways to pharmacologically mimic and enhance the protective mechanism of WldS . We hope this approach will offer an important route towards new treatments for glaucoma and other neurodegenerative diseases.
3. The role of disrupted axonal transport in glaucoma Our previous work suggests that elevated IOP causes interruption to retrograde axonal transport at the level of the optic nerve head. Dynein, the motor protein responsible for most retrograde axonal transport, accumulates at the optic nerve head in animal models of glaucoma. We are exploring the nature of the transport block in glaucoma and developing new imaging methods to allow the study of axonal transport in vivo in the living eye. We are currently using a wide range of techniques including paramagnetic nanoparticles traced by high resolution magnetic resonance imaging and adaptive optics imaging systems to allow the ultrastructure of individual cells to be visualised in the living retina. We are also using molecular biological techniques to probe the early changes that occur in response to elevated eye pressure to try to find new treatment approaches. 4. Neurotrophic factor gene therapy approaches to glaucoma We have previously pioneered new methods for highly efficient gene transfer to RGC. Using adeno-associated virus mediated expression of brain-derived neurotrophic factor, we were first in the world to demonstrate a protective effect of neurotrophic factor gene therapy in a model of glaucoma. In current work in collaboration with Robert MacLaren and Robin Ali ( Institute of Ophthalmology , London ) we are investigating the potential neuroprotective effects of gene therapy with other neurotrophic factors in glaucoma .
Research Group Post-doctoral scientists:
PhD students:
Collaborators
Key Publications Beirowski B, Babetto E, Coleman MP, Martin KR. The Wlds gene delays axonal but not somatic degeneration in a rat glaucoma model. Eur J Neurosci 2008 (in press) Martin KR. "Stem cells in glaucoma" in “Glaucoma” (First Edition), edited by Tarek Shaarawy, Mark B Sherwood, Roger Hitchings and Jonathan G. Crowston, Elsevier, 2008 (in press) Bull ND and Martin KR. Optic nerve restoration. J Glaucoma 2007 16(5):506-11. Bull ND and Martin KR. Human Müller stem cell (MIO-M1) transplantation in a rat model of glaucoma: survival, differentiation and integration. Invest Ophthalmol Vis Sci. 2008;49(8):3449-56 Johnson TV and Martin KR. Development and characterization of an adult retinal explant organotypic tissue culture system as an in vitro intraocular stem cell transplantation model. Invest Ophthalmol Vis Sci 2008;49(8):3503-12 Martin KR, Quigley HA, Valenta DF, Kielczewski J, Pease ME. Optic nerve dynein motor protein distribution changes with intraocular pressure elevation in a rat model of glaucoma. Exp Eye Res 2006;83(2):255-62. Levkovitch-Verbin H, Quigley HA, Martin KR, Harizman N, Valenta DF, Pease ME, Melamed S. The transcription factor c-jun is activated in retinal ganglion cells in experimental rat glaucoma. Exp Eye Res. 2005;80(5):663-70. Martin KR, Quigley HA, Zack DJ, Levkovitch-Verbin H, Kielczewski J, Valenta D, Baumrind L, Pease ME, Klein RL, Hauswirth WW. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 2003;44(10):4357-65. Levkovitch-Verbin H, Quigley HA, Martin KR, Valenta D, Baumrind LA, Pease ME. Translimbal laser photocoagulation to the trabecular meshwork as a model of glaucoma in rats. Invest Ophthalmol Vis Sci 2002;43(2):402-10. Martin KR, Levkovitch-Verbin H, Valenta D, Baumrind L, Pease ME, Quigley HA. Retinal glutamate transporter changes in experimental glaucoma and after optic nerve transection in the rat. Invest Ophthalmol Vis Sci 2002;43(7):2236-43. Levkovitch-Verbin H, Martin KR, Quigley HA, Baumrind LA, Pease ME, Valenta D. Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection. J Glaucoma 2002;11(5):396-405. Martin KR, Klein RL, Quigley HA. Gene delivery to the eye using adeno-associated viral vectors. Methods 2002;28(2):267-75. |
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