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| July 2004 | Inside IOVS | Volume 45/7 |
Identification of Neurons That May Regulate Eye Growth in Macaque Retina
Postnatal eye growth is regulated by visual feedback to produce a precise matching of axial length to optical power (emmetropia). Intrinsic retinal neurons, tuned to focus-dependent image features, are thought to generate locally-acting signals that retard or accelerate axial elongation. Zhong et al. (p. 2065) report the identification of retinal neurons that respond to focus and defocus in macaques, the best model for human refractive disorders. Further characterization of these neurons and their signaling systems, and confirmation that they participate in control of eye growth, could lead to new therapeutic approaches for preventing refractive disorders such as myopia and hyperopia.
Adenovirus-Mediated Gene Transfection of Corneal Stromal Cells
The efficient delivery and tissue-specific expression of exogenous genes in the cornea is an important step in the development of gene therapy for corneal diseases. Carlson et al. (p. 2194) show that intrastromal injection of adenoviral vectors can be used to easily transfect corneal stromal cells in vivo. Moreover, the keratocan promoter was used to drive in a tissue-specific fashion the expression of the enhanced green fluorescent protein in stromal keratocytes. These methods can be used to express genes of interest in corneal keratocytes in in vivo models of corneal disorders and assess their role in pathogenesis or therapeutic potential.
Predicting Glaucomatous Visual Fields from Optic Disc Evaluation
Some evidence suggests that glaucoma-related structural abnormalities of the optic disc evaluated by confocal scanning laser ophthalmoscopy, scanning laser tomography, or stereophotography, and evaluated by machine classifiers and regression analysis, precede the development of visual field defects measured using standard automated perimetry. These various methodologies, which appear to have high sensitivity and specificity, are presented in this issue by Bowd et al. (p. 2255) and by Tan et al. (p. 2279).
Bowd et al. [Abstract] [Full Text]
Tan et al. [Abstract] [Full Text]
Matrix Metalloproteinase-9 and Retinal Degeneration
Ganglion cell loss is a common end point in a number of ischemia-related disorders, including glaucoma. Previous studies have suggested that ischemia increases the extracellular concentrations of L-glutamate, which in turn excessively stimulates excitatory receptors ("excitotoxicity"), leading to calcium overload and neuronal cell loss. Using kainic acid, an L-glutamate analogue that activates specific receptors, Zhang et al. (p. 2374) demonstrate that kainic acid induces excitotoxic retinal damage through the up-regulation of matrix metalloproteinase-9 (MMP-9) in the retina. They demonstrate that this up-regulation of MMP-9 in part modulates the extracellular matrix within the ganglion cell layer and triggers apoptotic cell death initially in the ganglion cell layer and subsequently in the inner nuclear layer. Using non-NMDA antagonists and a synthetic MMP inhibitor, they also provide a causal link between excitotoxin mediated MMP-9 up-regulation and retinal degeneration. These findings raise the possibility of attenuating excitotoxin-mediated retinal degeneration by targeting MMP-9 in the retina.
Systematic Retinal Thickness Measurement Errors in the OCT3
Older models of the optical coherence tomograph (OCT) have been used to provide quantitative, qualitative, and reproducible information about retinal morphology at the posterior pole by using algorithm-based automated measurements. Costa et al. (p. 2399) demonstrate that the use of the automated measurement tool of the commercially available OCT3 system to assess retinal thickness significantly underestimates such values due to incorrect software interpretation of the outer boundary of the neurosensory retina. Therefore, all OCT3 data from published as well as forthcoming studies using this measurement tool should be interpreted with caution.
STAT3 in Rod Photoreceptor Determination
Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor can specifically block the production of rod photoreceptors in both mice and chicks. However, the pathways used to transduce their signals into the cell are not understood. Here, Zhang et al. (p. 2407) found that blocking of the MAPK pathway did not affect development of rods in retina explants or the suppression of their appearance by CNTF. In contrast, activated STAT3 is necessary for suppression of the rod fate decision. A deficiency of the STAT3 pathway abolished inhibition of rod development by CNTF. These results indicate that STAT3, but not MAPK, can critically regulate photoreceptor development during mouse retina development.
Effect of NF-kB Inhibition on TNF-a-Induced Apoptosis in Human RPE Cells
Tumor necrosis factor (TNF-a) is an important cytokine associated with proliferative vitreoretinopathy (PVR). The nuclear transcription factor-kB (NF-kB) is a pivotal regulator of cytokines and apoptosis. NF-kB blockade enhances TNF-a-induced apoptosis in a variety of cell types otherwise resistant to TNF-a-induced apoptosis. To understand mechanisms responsible for RPE cell survival and death in PVR, Yang et al. (p. 2438) used an adenoviral vector that encodes a mutant IkB, showing that RPE cells are resistant to TNF-a-induced cell death even after specific NF-kB blockade. RPE cell resistance to apoptotic signals present in eyes with PVR may help to explain uncontrolled cell proliferation in this disease.
New Hope for Uveal Melanoma Treatment: Blocking the Action of c-Kit
The multi-step development of tumors involves numerous changes at the genomic level, such as oncogene activation and loss of function of tumor suppressor genes. However, in the cellular processes that lead to cancer it is likely that the cancer cells make use of normal extracellular signaling pathways to stimulate proliferation and/or anti-apoptosis. In this way cancer cells create possess a growth advantage over the normal cells. As reported by All-Ericsson et al. (p. 2075), c-kit and its ligand, stem cell factor (SCF) generate such a signaling pathway in uveal melanoma cells. The authors demonstrate that blocking c-kit can decrease the proliferation and viability of uveal melanoma cells. These data suggest c-kit as a novel therapeutic target for treatment of uveal melanoma.
New Insights into Rod Outer Segment Uptake by the Retinal Pigment Epithelium
Although multiple genes are likely involved in rod outer segment (ROS) uptake by the retinal pigment epithelium (RPE), only a handful have been described. Chowers et al. (p. 2098) identified multiple RPE gene expression alterations in association with ROS uptake. Interestingly, these expression changes showed gene specific kinetics. Plasminogen activator inhibitor 1 (PAI1), one of the genes up-regulated after ROS uptake, showed protein level alterations that correlated with the mRNA changes, and recombinant PAI1 inhibited ROS binding to RPE cells. These findings demonstrate the molecular complexity of ROS uptake and degradation by the RPE, and provide a candidate protein for participation in a negative feedback mechanism for ROS binding to the RPE.
Oxidative Damage Does Not Affect the Chaperone Activity of Lens a-Crystallin
Peroxynitrite is a potent reactive oxygen/nitrogen species, produced endogenously in the eye, causing oxidative damage and consequent eye disorders. Thiagarajan et al. (p. 2115) have studied the reaction of peroxynitrite with the crystallins of the eye lens. Oxidation leads to the formation of nitro-tyrosine, nitro-tryptophan, dityrosine, covalent cross-links and chain degradation, and is seen to occur in the order g > b > a-crystallin. Even though a-crystallin suffers oxidative damage upon reaction with peroxynitrite, its chaperone activity is not lost. The structural and functional robustness of a-crystallin appear to have been selected through evolution, particularly in the lens, where molecular turnover is extremely sluggish.
Disruption of Schlemm's Canal Cells and IOP
What controls aqueous outflow? Both the extracellular matrix and Schlemm's canal cells have been theorized as the key factor in creating intraocular pressure. Bahler et al. (p. 2246) targeted Schlemm's canal cells for disruption by pharmacologically weakening the cytoskeleton and allowing the normal pressure gradient the cells face to push them from their position. Facility of outflow increased, but not as much as predicted if the canal cells were the only determinant of outflow. A simple relationship between canal cells and facility was not found; canal cells probably interact with the extracellular matrix in influencing outflow facility.
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