PURPOSE. The aim of the present study was to identify candidate genes for mediating daily adjustment of vision. METHODS. Genes important for vision and genetically associated with severe retinal diseases were tested for 24-hour rhythms in transcript levels in neuronal retina, microdissected photoreceptors, photoreceptor-related pinealocytes, and retinal pigment epithelium-choroid (RPE-choroid) complex by using quantitative PCR. RESULTS. Photoreceptors of wildtype mice display circadian clock-dependent regulation of visual arrestins (Arr1, Arr4) and the visual cycle gene Rdh12, whereas cells of the RPE-choroid exhibit light-dependent regulation of the visual cycle key genes Lrat, Rpe65, and Rdh5. Clock-driven rhythmicity of Arr1, Arr4, and Rdh12 was observed also in rat pinealocytes, to persist in a mouse model of diabetic retinopathy (db/db) and, in the case of Arr1, to be abolished in retinae of mice deficient for dopamine D4receptors. Therefore, the expression rhythms appear to be evolutionary conserved, to be unaffected in diabetic retinopathy, and, for Arr1, to require dopamine signaling via dopamine D4 receptors. CONCLUSIONS. The data of the present study suggest that daily adjustment of retinal function combines clock-dependent regulation of genes responsible for phototransduction termination (Arr1, Arr4) and detoxification (Rdh12) in photoreceptors with light-dependent regulation of genes responsible for retinoid recycling (Lrat, Rpe65, and Rdh5) in RPE. Furthermore, they indicate circadian and light-dependent regulation of genes genetically associated with severe retinal diseases.
by
Darryl R. Overby;
Enhua H. Zhou;
Rocio Vargas-Pinto;
Ryan M. Pedrigi;
Rudolf Fuchshofer;
Sietse T. Braakman;
Ritika Gupta;
Kristin M. Perkumas;
Joseph M. Sherwood;
Amir Vahabikashi;
Dang Quynh;
Jae Hun Kim;
Ross Ethier;
W. Daniel Stamer;
Jeffrey J. Fredberg;
Mark Johnson
Increased flow resistance is responsible for the elevated intraocular pressure characteristic of glaucoma, but the cause of this resistance increase is not known. We tested the hypothesis that altered biomechanical behavior of Schlemm's canal (SC) cells contributes to this dysfunction. We used atomic force microscopy, optical magnetic twisting cytometry, and a unique cell perfusion apparatus to examine cultured endothelial cells isolated from the inner wall of SC of healthy and glaucomatous human eyes. Here we establish the existence of a reduced tendency for pore formation in the glaucomatous SC cell-likely accounting for increased outflow resistance-that positively correlates with elevated subcortical cell stiffness, along with an enhanced sensitivity to the mechanical microenvironment including altered expression of several key genes, particularly connective tissue growth factor. Rather than being seen as a simple mechanical barrier to filtration, the endothelium of SC is seen instead as a dynamic material whose response to mechanical strain leads to pore formation and thereby modulates the resistance to aqueous humor outflow. In the glaucomatous eye, this process becomes impaired. Together, these observations support the idea of SC cell stiffness-and its biomechanical effects on pore formation-as a therapeutic target in glaucoma.
Purpose:
Juvenile idiopathic arthritis (JIA)-associated uveitis can lead to ocular complications and vision loss. Alleles HLA-DRB1*08, *11, and *13 are risk alleles for JIA, whereas HLADRB1* 11 and *13 alleles increase uveitis susceptibility. We examined the association of common HLA-DRB1 alleles in children with JIA alone and JIA-associated uveitis.
Methods:
High-resolution HLA-DRB1 genotyping was performed in 107 children with oligoarticular and polyarticular rheumatoid factor (RF) negative JIA and 373 non-Hispanic white controls. Children with JIA alone and JIA-associated uveitis were of similar race, ethnicity, sex, and age at arthritis diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated.
Results:
There were 47 children with JIA-associated uveitis and 60 with JIA alone. Compared to controls, only childrenwith JIA-associated uveitis had increased odds of carriage ofHLA-DRB1*11 (OR, 2.2 95% [CI, 1.1-4.3], P = 0.023). There also was increased carriage of HLA-DRB1*08 and *13 (OR, 12.6 [95% CI, 2.0-77.8], P = 0.011). Compared to controls and children with JIA alone, those with JIA-associated uveitis had increased odds of carriage of HLA-DRB1*11 and *13 (OR, 9 [95% CI, 2.8-29.0], P < 0.0001 and OR, 8.6 [95% CI, 1.0-74.4], P = 0.042), respectively.
Conclusions:
We report the novel finding that carriage of HLA-DRB1*11 and *13 appears to increase the risk of uveitis in children with JIA.
Purpose.
We described anatomic age-related changes in the human eye to determine potential areas of investigation that may lead to identifying eyes at risk for age-related disease.
Methods.
A descriptive review of anatomic changes in the eye related to aging was performed in the context of current areas of investigation. The review was performed specifically for differing anatomic ocular structures, including cornea, trabecular meshwork, lens, uveal tract, Bruch's membrane, retina, RPE, vitreous, sclera, and optic nerve.
Results.
Age-related changes occur in all ocular tissues. The cornea flattens and there is an attrition of endothelial cells. The shape of the trabecular meshwork changes and there is a loss of trabecular endothelium. The lens grows and becomes cataractous. The ciliary body becomes collagenized, there are choroidal vascular changes, and Bruch's membrane thickens. Retinal vessels become hyalinized and there is a loss of rods before cones in the macula. RPE morphometric changes occur with aging. The vitreous becomes liquefied and there is a loss of vitreous compartmentalization. The sclera becomes rigid and may become calcified. The optic nerve exhibits structural changes with age.
Conclusions.
There are numerous anatomic age-related changes in the human eye. Current areas of investigation related to these changes include adaptive optics scanning laser ophthalmoscopy imaging of the RPE mosaic in the context of aging, and drug delivery devices that overcome age-related alterations to retinal and macular perfusion.