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| May 2006 | Inside IOVS | Volume 47/5 |
Biochemistry of Altered Eye Growth
Many studies suggest that postnatal ocular growth is guided by visual experience and involves a cascade of biochemical signals from the retina, the retinal pigment epithelium (RPE) and choroid, which act to alter scleral extracellular matrix remodeling ultimately altering eye size and refractive state. In this issue, Troilo et al. (p. 1768) have examined the relationship between retinoic acid, scleral glycosaminoglycan synthesis, and the rate of ocular growth in the eyes of juvenile marmoset monkeys undergoing different rates of axial elongation. Results of their studies suggest that retinoic acid is likely to play a role in the visual control of eye growth, and the biochemical mechanisms mediating increased ocular elongation rates may be distinct from those involved in decreasing ocular growth rates.
How Much Is Enough? Molecular Dissection of Pitx2 Gene Dose
PITX2 gene dose plays a central role in Axenfeld-Rieger syndrome and glaucoma but the underlying molecular mechanisms are unknown. Diehl et al. (p. 1785) have tested the hypothesis that the effects of Pitx2 gene dose on eye development can be molecularly
dissected in available Pitx2 mutant mice. Their results document extraocular muscle as the first ocular tissue affected by Pitx2 gene dose in a model organism, where the underlying mechanisms can be analyzed, and provide a paradigm for future experiments designed to elucidate additional effects of Pitx2 gene dose during eye development.
Annexin A5 Promotes Corneal Epithelial Wound Healing
Watanabe et al. (p. 1862) have shown that annexin A5, a calcium-dependent phospholipid-binding protein, promotes the migration of rabbit corneal epithelial cells in vitro. Moreover, in rabbit corneal wound closure models, the healing rate was significantly increased by instillation of eye drops containing annexin A5 compared with that apparent in the eyes that received vehicle. Annexin A5 also increased the release of uPA from wounded RCE cell monolayers. Upregulation of uPA release from corneal epithelial cells may contribute to this effect of annexin A5.
A Synthetic Corneal Substitute
Corneal blindness affects over 10 million people worldwide and is treated by donor cornea transplantation. Because of a growing world shortage of donated corneas, Liu et al. (p. 1869) developed an artificial substitute that could be made easily at centers needing transplants or temporary patches to repair perforations in emergency situations. Their substitutes comprise crosslinked collagen and are molded into optically clear cornea shapes. When transplanted into 24 animals, corneas remained transparent and robust over a 6-month period, with only one implant showing faint haziness. All implants promoted regeneration of corneal cells, tear film and nerves and integrated with the hosts' tissue.
A Model of Potassium Secretion by Lacrimal Gland Ducts
The fluid secreted by the lacrimal gland has a high potassium ion concentration, in excess of 20 mEq/L. It is thought that the ducts of the lacrimal gland are responsible for secretion of potassium, but because of their small size and inaccessibility, relatively little is known about the function of these cells. Ubels et al. (p. 1876) isolated duct cells by laser capture microdissection followed by analysis of gene expression with cDNA microarrays. Using gene ontologies related to ion transport, a panel of genes involved in K+ and Cl- was identified in the duct cells. By immunofluorescence, several channels and transport proteins were localized in the duct cell membranes allowing construction of a model consistent with secretion of potassium into the lumen of the lacrimal gland ducts.
Extracellular Chaperone Deficiency in Eyes with Pseudoexfoliation Syndrome
Pseudoexfoliation (PEX) syndrome, the most commonly identified specific cause of open-angle glaucoma, is characterized by the intra- and extraocular deposition of an abnormal fibrillar extracellular material. Zenkel et al. (p. 1982) report the significantly reduced expression of the extracellular chaperone clusterin in early stages of PEX syndrome and demonstrate the in vitro downregulation of clusterin by TGF-b1. Chaperone deficiency in the anterior segment of PEX eyes, possibly mediated by increased aqueous TGF-b1 levels, may promote the aggregation and stable deposition of PEX material in the sense of a conformational disorder.
N-Chlorotaurine as a Potential Anti-Adenoviral Agent
Adenovirus ocular infections are the most common ocular viral infections worldwide. At present, there is no FDA-approved antiviral treatment for these infections. N-Chlorotaurine (NCT) is the N-chloro derivative of the amino acid taurine. It is an essential, weak, long-lasting oxidant produced by human granulocytes and monocytes during inflammatory reactions. The study of Romanowski et al. (p. 2021) attempted to determine whether NCT possesses antiviral activity against adenovirus in vitro and in the Ad5/NZW rabbit ocular model. The results of this study demonstrated that NCT possessed potent antiviral activity against adenovirus in vitro and in vivo. Further development of NCT as a topical antimicrobial is indicated.
Altered Transferrin Expression in Age-Related Macular Degeneration
Iron overload has been implicated in several neurodegenerative disorders including age-related macular degeneration (AMD). Chowers et al. (p. 2135) have compared the expression of transferrin, an iron carrier, between retinas of AMD patients and unaffected individuals. The study demonstrated increased transferrin expression in AMD at the mRNA and protein levels. These data, combined with previous reports on iron accumulation in retinas of AMD patients and the development of AMD-like features in retinas of patients and mice with iron overload, suggest that alterations in iron metabolism are associated with AMD. While the role of such alterations in the pathogenesis of the disease is still unclear, an interesting hypothesis with potential therapeutic ramifications is that iron may accelerate oxidative injury to the retina in AMD.
F-actin Disruption and IOP
Recent work shows that F-actin depolymerizing agents increase outflow facility and lower IOP in primate and other animal eyes. Ethier et al. (p. 1991) show that the same effect occurs in post-mortem human eyes. How does this happen? Histology shows loss of cell-cell and cell-matrix adhesion, manifesting as "loosening" of the trabecular meshwork and an increase in intercellular pores in the inner wall of Schlemm's canal. Although the magnitude of the facility increase seen in post-mortem human eyes was less than that previously reported in the living monkey, this result holds hope for new pressure-lowering drugs in humans.
The Human Photoreceptor Mosaic in Retinal Dystrophies
Choi et al. (p. 2080) show adaptive optics images of the human retina with various forms of retinal dystrophies. This objective measurement of cone photoreceptor integrity and density were found to be highly correlated with measures of retinal function taken with standard clinical and research tests. The results show the potential effectiveness of adaptive optics imaging for detecting and measuring the severity of retinal dystrophies. In vivo retinal imaging at the cellular level opens the possibility of (1) a more sensitive method for quantifying retinal changes, (2) earlier detection of any changes, (3) monitoring new therapeutic regimens, and (4) the visualization of cellular changes without introducing artifacts from in vitro preparations.
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