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| August 2007 | Inside IOVS | Volume 48/8 |
Minimal Changes in Retinal Gene Expression in Experimental Myopia
Using genome-wide microarray profiling of retina/RPE transcripts, McGlinn et al. (p. 3430) found that form deprivation myopia in chick is associated with minimal changes in gene expression at the RNA level. While the list of validated genes is short, each merits further study for potential involvement in the signaling cascade linking the retina to myopia development. These results raise the possibilities that major changes in retinal gene expression may not be required for human myopia and that, given temporal differences in differential gene expression in chick, mechanisms of myopia onset may differ from those responsible for myopia progression. Several candidate genes for human myopia are suggested.
Bacterial DNA Protects Injured Optic Nerve
The study by Johnson et al. (p. 3441) represents a surprising evolutionary adaptation whereby opportunistic bacterial infiltration following central nervous system (CNS) injury might prevent neuronal loss. This is the first time that toll-like receptors (TLRs) have been directly linked to neuroprotection. This study may lead to the development of novel therapeutic strategies for the damaged CNS that utilize the unique ability of TLR ligands to boost a protective immune response and to prevent neuronal death in acute and chronic neurodegeneration.
Distribution of Neuromuscular Junctions in Extraocular Muscles
The architectural arrangement within extraocular muscles (EOMs) has important implications for understanding length-tension relationships, shortening velocities, and the development of force within the EOMs. Harrison et al. (p. 3594) reconstructed the density and distribution of neuromuscular junctions (NMJs) in normal rabbit and monkey EOM in three dimensions using serial sections cut longitudinally. The NMJs are much more extensive in their location and density than previously described. Individual myofibers are significantly shorter than the tendon-to-tendon muscle length in both muscle layers. Botulinum toxin results in a doubling of NMJ density. Clarification of the NMJ localization in normal EOM has ramifications for understanding eye movement control, but it is also important when surgical or pharmacologic interventions are used for the treatment of strabismus, nystagmus, or other eye muscle disorders.
Endothelin-1 and Excellular Matrix Remodeling in Astrocytes
The mechanisms leading to the pathophysiology of glaucoma are still unclear. Accompanying neuropathological changes in the optic nerve are associated changes in the extracellular matrix (ECM). Evidence shows that one class of enzymes, matrix metalloproteinases (MMPs), may play an important role in regulating the ECM. He et al. (p. 3737) report that endothelin-1, a vasoactive peptide, appears to control the activity of this class of enzymes in astrocytes, the major supporting cells in the optic nerve head. It is reported that endothelin-1 increases the activity of MMPs and their corresponding inhibitors, tissue inhibitor of MMPs. It is suggested that controlling the level of endothelin-1 and activity of MMPs may be a promising approach in the treatment of glaucoma.
Manganese-Enhanced MRI in the Diagnosis of Retinal Injury
There is a fundamental need in the study of retinopathy for a non-invasive imaging method that is capable of simultaneously and non-invasively assessing the effects of retinal insult on layer-specific thickness and activity. Berkowitz et al. (p. 3796) report that manganese-enhanced MRI, using systemically administered and non-toxic dose of manganese, can address this need in models of ocular injury. The availability of this new tool is expected to benefit investigators studying a range of retinopathies.
Natural History and Gene Therapy in XLRS Mouse Model
The retinoschisin (Rs1h) knockout mouse is a model of X-linked retinoschisis (XLRS), a leading cause of macular degeneration in young males. Kjellstrom et al. (p. 3837) show that these Rs1h-deficient mice have dynamic inner retinal and photoreceptor structural alterations over time that are correlated with changes in electroretinogram (ERG) function. Rs1h gene therapy at an early age produced high levels of Rs1h expression in photoreceptors and substantial photoreceptor rescue with less ERG amplitude decline for over one half of the animal’s lifespan. This study adds new information about the natural history of XLRS disease and the possible benefits of retinoschisin gene therapy.
Bcl-xL Is an Important Human Retinal Pigment Epithelial Cell Survival Protein
Retinal pigment epithelial (RPE) cell survival is critically important in normal eyes and in diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Bcl-xL is a key anti-apoptotic member of the Bcl-2 family that regulates the intrinsic apoptosis pathway. Zhang et al. (p. 3846) found that Bcl-xL is a crucial mediator of human RPE cell survival under normal conditions and when cells are exposed to oxidative stress. Bcl-xL may be an important target to prevent RPE cell death in AMD and to inhibit pathological RPE cell survival in PVR.
Innervation of Implanted, Tissue-Engineered Corneal Substitutes
The pattern of reinnervation within biodegradable crosslinked-collagen corneal substitutes over 12 months was reported by Lagali et al. (p. 3537). The study revealed an initial in-growth of stromal nerves into the implant area, followed by reinnervation of the subepithelial region and finally, in-growth into the epithelial compartment to reconstitute preoperative levels. A simple scaffold reproducing the corneal extracellular matrix, in this case collagen, was therefore able to promote substantive neural regeneration after lamellar keratoplasty. Such simple but biomimetic scaffolds have the potential to be developed into viable, long-term substitutes to allogenic donor corneal tissue.
Neuroprotection in Optic Neuritis by SIRT1 Activation
A novel therapy to prevent neuronal loss during optic neuritis in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is described. Optic neuritis is an inflammatory disease that can cause permanent vision loss due to neuronal death. Current therapies for MS and optic neuritis target inflammatory components of disease, with limited ability to prevent neurodegeneration. Schindler et al. (p. 3602) demonstrate that SIRT1 activators attenuate loss of retinal ganglion cells and preserve axonal function without preventing optic nerve inflammation. These neuroprotective effects provide a novel therapeutic approach to preventing neurological disability in optic neuritis and MS, potentially additive to current immunomodulatory therapies.
Achromatopsia Due to CNGB3 Gene Mutations
Achromatopsia associated with mutations in the CNGB3 gene is an autosomal recessive congenital trait characterized by compromised color discrimination, reduced visual acuity, nystagmus, and photophobia. CNGB3 encodes the b-subunits of the cyclic nucleotide-gated (CNG) channel located on cone photoreceptors. As reported by Khan et al. (p. 3864), extended phenotyping of individuals with this type of channelopathy showed macular atrophy beyond any level previously reported. Some individuals retained cone function by the ERG into adult years and showed progressive loss in middle age. Although the CNGB3 protein is known to be expressed only on cone photoreceptors, the rod-driven ERG was abnormal both at the level of a- and b-wave. There was a clear manifestation of the carrier state in both young and older age. Carrier states are rarely reported for autosomal recessive retinopathies.
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