Oxidative Stress and Inflammation-Related mRNAs Are Elevated in Serum of a Finnish Wet Age-Related Macular Degeneration Cohort
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ABSTRACT:
PROVIDER: PRJNA1141914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30037900_1.fastq.gz | Fastqsanger.gz | |||
| SRR30037900_2.fastq.gz | Fastqsanger.gz | |||
| SRR30037901_1.fastq.gz | Fastqsanger.gz | |||
| SRR30037901_2.fastq.gz | Fastqsanger.gz | |||
| SRR30037902_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Localized diseases are affected by and affect the systemic environment via blood circulation. In our studies, we explored the differences in different types of circulating serum RNAs between wet age-related macular degeneration (wAMD) patients and controls. Methods: Blood samples were obtained from 60 Finnish wAMD patients and 64 controls. After serum preparation and RNA sequencing, the count data was examined for differentially expressed genes (DEGs) and further checked for enriched molecular pathways and ontology terms as well as links to clinical data. Results: In our mRNA study, we found many DEGs and some enriched pathways, including the inflammation and cell survival-associated pathway tumor necrosis factor alpha (TNFA) signaling via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). The related DEGs were oxidized low-density lipoprotein receptor 1 (OLR1), salt inducible kinase 1 (SIK1), and coagulation factor III (F3). DEGs from degradative macular and retinal processes were also examined, many of which were also related to cardiovascular disease and maintenance. Additionally, DEG counts were inspected in relation to clinical and anti-vascular endothelial growth factor (anti-VEGF) treatment parameters, and glutamine amidotransferase-like class 1 domain-containing 3A (GATD3A) levels were found to be significantly lower in wAMD patients who had been receiving anti-VEGF treatments compared to those who had not yet received any. Conclusions: Since regulatory factors of mitochondrial function, oxidative stress, and inflammation have a significant role in the pathology of AMD, our mRNA study results may support the presence of interplay between systemic factors and wAMD development and progression.
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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruchâs membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruchâs membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found â564â differentially expressed genes of which â190â were up-regulated and â374â were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model. All 5XFAD mice used were heterozygotes with respect to the transgene, and non-transgenic wild-type littermate (WT) mice served as controls.
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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. There are two types of AMD: dry AMD and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD by presenting the main features of human wet AMD, there was no established mouse model which fully recapitulates the cardinal features of human dry AMD. In this regard, lack of appropriate mouse model for dry AMD hampered the translational research on the pathogenesis and development of therapeutic agents. We recently suggested that 5XFAD mice could be a mouse model of dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, using transmission electron microscope, we analyzed ultrastructure of retinal pigment epithelium (RPE) of 5XFAD mice. Of importance, aged 5XFAD mice had ultrastructural changes of RPE and Bruch’s membrane compatible with cardinal features of dry AMD, including loss of apical microvilli and basal infolding of RPE, increased thickness of Bruch’s membrane, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laiden phagosomes. Using a threshold of 1.2 fold difference, we found “564” differentially expressed genes of which “190” were up-regulated and “374” were down-regulated in the RPE complex of aged 5XFAD mice. These altered genes were implicated in the pathogenesis of AMD including inflammation and immune response-related genes and retinol metabolism-related genes. Taken together, we suggest that aged 5XFAD mice can be used for dry AMD mouse model.
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Project description:Age-related macular degeneration (AMD) is a leading cause of human blindness in developed countries. While significant inroads have been made over the past decade, an integrated description of the molecular mechanisms underlying AMD has yet to emerge. Here we describe a systems-level transcriptome analysis of the retina and retinal pigmented epithelium (RPE)-choroid complex from 31 normal, 26 AMD, and 11 potential pre-AMD human eyes derived from the University of Iowa. Our analysis identifies cell-mediated immune responses as the central feature of dry AMD, wet AMD, and geographic atrophy (GA), and we confirm this finding using a second cohort of donor eyes obtained from the Lion's Eye Bank of Oregon. In addition, in the RPE-choroid, we identify the major up-regulated pathways in GA and wet AMD as apoptosis and angiogenesis, respectively. In the retina, a graded up-regulation of wound response, complement, and neurogenesis pathway genes strongly correlates with advanced stages of AMD, in parallel with a progressive down-regulation of key phototransduction processes. Finally, using expression signatures enriched in functional pathways, we assemble two detailed AMD interactomes that highlight modular gene expression programs that delineate and interconnect dry, wet, and GA AMD subtypes across both RPE-choroid and retina tissues. In total, these interactomes are comprised of over 150 genes of which 23 have been previously associated with AMD. These data provide new insights into the expression landscape of AMD pathophysiology, and reveal numerous new targets for AMD pharmaceuticals and diagnostics.
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Project description:Age-related macular degeneration has a strong epidemiological association with cardiovascular disease. One pathogenic hypothesis that applies to both diseases is the concept of an abnormal cellular response to injury resulting in a disease phenotype. It has been hypothesized that this phenotype is also present in dermal fibroblasts. This study tests this hypothesis by examination of the expression profiles of fibroblasts obtained from diseased patients and subjected to sublethal cell injury.
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Project description:Age-related macular degeneration is an eye disease that is the main cause of legal blindness in the elderly in developed countries. Despite this, its pathogenesis is not completely known, and many genetic, epigenetic, environmental and lifestyle factors may be involved. Vision loss in age-related macular degeneration (AMD) is usually consequence of the occurrence of its wet (neovascular) form that is targeted in the clinic by anti-VEGF (vascular endothelial growth factor) treatment. The wet form of AMD is associated with the accumulation of cellular waste in the retinal pigment epithelium, which is removed by autophagy and the proteosomal degradation system. In the present work, we searched for the association between genotypes and alleles of single nucleotide polymorphisms (SNPs) of autophagy-related genes and wet AMD occurrence in a cohort of Finnish patients undergoing anti-VEGF therapy and controls. Additionally, the correlation between treatment efficacy and genotypes was investigated. Overall, 225 wet AMD patients and 161 controls were enrolled in this study. Ten SNPs (rs2295080, rs11121704, rs1057079, rs1064261, rs573775, rs11246867, rs3088051, rs10902469, rs73105013, rs10277) in the mTOR (Mechanistic Target of Rapamycin), ATG5 (Autophagy Related 5), ULK1 (Unc-51-Like Autophagy Activating Kinase 1), MAP1LC3A (Microtubule Associated Protein 1 Light Chain 3 α), SQSTM1 (Sequestosome 1) were analyzed with RT-PCR-based genotyping. The genotype/alleles rs2295080-G, rs11121704-C, rs1057079-C and rs73105013-T associated with an increased, whereas rs2295080-TT, rs2295080-T, rs11121704-TT, rs1057079-TT, rs1057079-T, rs573775-AA and rs73105013-C with a decreased occurrence of wet AMD. In addition, the rs2295080-GG, rs2295080-GT, rs1057079-TT, rs11246867-AG, rs3088051-CC and rs10277-CC genotypes were a positively correlated cumulative number of anti-VEGF injections in 2 years. Therefore, variability in autophagy genes may have an impact on the risk of wet AMD occurrence and the efficacy of anti-VEGF treatment.
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Project description:Age-related macular degeneration has a strong epidemiological association with cardiovascular disease. One pathogenic hypothesis that applies to both diseases is the concept of an abnormal cellular response to injury resulting in a disease phenotype. It has been hypothesized that this phenotype is also present in dermal fibroblasts. This study tests this hypothesis by examination of the expression profiles of fibroblasts obtained from diseased patients and subjected to sublethal cell injury. Keywords: other
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