No description available.

No description available.

Age-related macular degeneration (AMD) is the most common cause of vision loss in America for people over the age of 60. Due to damage to the retina, symptoms normally include blurred central vision, difficulty reading, and seeing shadows. While there is no cure for the disease, there are treatments that slow its progression and can restore vision. The treatments explored in this paper are: anti-vascular endothelial growth factor (VEGF) drugs, photodynamic therapy (PDT) and steroids. All three require invasive eye procedures that carry their own risks. The possibility of more effective treatments by combining these therapies is being tested through clinical trials. Studies of combined PDT and anti-VEGF, combined PDT and steroids, and anti-VEGF monotherapy were reviewed, comparing changes in average visual acuity, foveal thickness, and number of injections administered. PDT and anti-VEGF was concluded to be the most efficient of the three, requiring fewer injections while showing an increase in visual acuity similar to anti-VEGF monotherapy.

No description available.

No description available.

Age-related Macular Degeneration (AMD) is the leading cause of irreversible vision loss among elderly people in developed countries. The non-neovascular or “dry” form of AMD accounts for 85%, whereas the neovascular or “wet” accounts for 15%, of all cases. There are no effective treatments for dry AMD mainly because the molecular mechanisms that lead to the development and progression of AMD are not fully understood. Similarly, while wet AMD is being treated with antibodies against vascular endothelial growth factor (VEGF), the underlying cause that results in the development of wet AMD remains elusive. Cytosolic accumulation of nuclear-DNA (nDNA) fragments has been found to trigger inflammation and mediate the development of multiple diseases. Because inflammation plays a pivotal role in AMD pathogenesis, we thus investigated if accumulation of cytosolic nDNA also contributes to AMD. Our data show that cytosolic nDNA is enriched in macular retinal pigment epithelium (RPE) cells of AMD patients. To study the effect of cytosolic nDNA on RPE cells, we mimicked this pathology by deleting the lysosomal endonuclease Dnase2a, which is responsible for degrading DNA fragments, using CRISPR/Cas9. This resulted in cytosolic accumulation of nDNA in cultured primary human RPE cells as well as in the RPE cell line ARPE-19. Importantly, both RPE cell types with Dnase2a loss became senescent and secreted higher levels of VGEF and pro-inflammatory cytokines compared to control. These effects were mediated by the DNA sensor STING and mTOR pathway. Additionally, similar to other senescent cells, these senescent RPE cells secreted factors that acted in a paracrine manner turning otherwise healthy RPE cells into senescent cells that start secreting VEGF as well as pro-inflammatory cytokines. Finally, we found that mice with Dnase2a deletion develop features of AMD-like retinopathy, including drusen- like deposits, thickened Bruch’s membrane, RPE damage, photoreceptor atrophy, and reduced electroretinogram. The pleiotropic downstream effects of cytosolic accumulation of nDNA in RPE cells, which are consistent with the complex AMD pathology, suggest that this phenomenon contributes to the pathogenesis of AMD and thereby opens new opportunities for therapeutic interventions. / 2020-10-24T00:00:00Z

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No description available.

The purpose of this study is to examine the association between serum bilirubin and the development of age-related macular degeneration (AMD). The study design includes the utilization of a USA-nationally representative population based cross-sectional study in the National Health and Nutrition Examination Survey: specifically, the NHANES III and continuous NHANES from years 2005-2008. 15,501 survey participants from the NHANES studies chosen for this analysis were interviewed for demographic, behavioral, and medical information, put through a comprehensive medical examination segment, and a laboratory analysis portion. The 15,501 participants were chosen based on their age (40 and above) and the presence of fundus photographs. Fundus photographs were graded using standardized protocol to diagnose early and later AMD, which were combined to form the outcome "AMD" in a binary variable. Serum bilirubin levels were measured using spectrophotometry. Of the 15,501 participants in the study, 1305 (8.9%) were diagnosed with AMD. In a multivariate logistic regression adjusted for age, sex, smoking status, race, and serum C-reactive protein (CRP) levels, bilirubin was significantly associated with AMD (odds ratio, 0.728; confidence interval, 0.547-0.969; P value, 0.0296). The findings of this study indicate that the antioxidative effects of bilirubin may play protective role in the pathology of AMD.

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years. Environmental and genetic risk-factors contribute to the development of AMD. An AMD-risk locus on chromosome 10q26 spans two genes, ARMS2 and HTRA1, and controversy exists as to which variants are responsible for increased risk of disease. Recent work suggests that HTRA1 expression levels are significantly increased in carriers of the risk haplotype associated with AMD. However, relatively little is known about the interactions, substrate specificity and roles in disease played by this secreted serine protease. This thesis aims to elucidate the potential role played by HTRA1 in AMD pathogenesis. A combination of tandem affinity purification (TAP) and yeast two-hybrid techniques was used to identify interacting partners of HTRA1. A number of proteins, with diverse roles in the alternative complement pathway, cell signaling, cell-matrix interactions, inflammation, angiogenesis and fibrosis, were identified. These are attractive candidates for further study as such processes are disturbed in AMD, implicating HTRA1 and its binding partners in disease development. One interacting partner, Complement Factor D (CFD), is a key activator in the alternative complement pathway. CFD, a 24 kDa serine protease, is expressed as an inactive zymogen, from which a signal peptide and activation peptide are cleaved before release of the mature, active protein into the circulation. In vitro studies show that CFD interacts with, and can be a substrate for, HTRA1. The interacting domain between the two proteins is localised to a region of 30 amino acids at the N-terminal end of proCFD. The 5 amino acid pro-peptide of CFD appears to be both necessary and sufficient for proteolysis of CFD by HTRA1. Investigation of the functional relevance of the interaction between HTRA1 and CFD shows that proCFD is cleaved by HTRA1, whilst mature CFD is not subjected to proteolysis. HTRA1-mediated cleavage of CFD forms an active protease, leading to activation of factor B in the alternative complement pathway in in vitro assays. Furthermore, a normal complement response is restored to CFD-depleted serum by addition of proCFD activated by HTRA1. Thus, an HTRA1- mediated increase in alternative complement pathway activity may explain a proportion of the AMD-risk attributed to the chr10q26 locus. Genetic and protein-based approaches were used to study the potential role of CFD in AMD pathogenesis, independent of an interaction with HTRA1. An intronic SNP, rs3826945, was significantly associated with increased risk of AMD in two British case-control cohorts, and in a combined meta-analysis with 4 additional cohorts from North America and Europe (p-value = 0.032, Odds Ratio = 1.112 in 4765 cases and 2693 controls). Assessment of copy number variation and sequencing of CFD did not identify any functional variants which may explain the association with disease. However, plasma levels of CFD were measured by ELISA in 751 AMD cases and 474 controls, and were found to be significantly elevated in AMD cases compared to controls (p-value = 0.00025). This further implicates complement activation in AMD pathogenesis, and makes CFD an attractive candidate for therapeutic intervention. An alteration in the level of activated CFD, possibly mediated via an interaction with HTRA1, either at the systemic or local tissue level, may play a role in disease development and progression.