Investigative ophthalmology & visual science最新文献

{"title":"Preclinical Evaluation of Pitavastatin Nanoparticles for Preserving Cone Photoreceptors in Mouse Models of RP.","authors":"Sakurako Shimokawa, Masatoshi Fukushima, Shotaro Shimokawa, Takahiro Hisai, Yan Tao, Huanyu Zhao, Jun Funatsu, Shoji Notomi, Keijiro Ishikawa, Mitsuru Arima, Chie Kikutake, Mikita Suyama, Kaori Tanaka, Yasuyuki Ohkawa, Koh-Hei Sonoda, Yusuke Murakami","doi":"10.1167/iovs.66.13.15","DOIUrl":"https://doi.org/10.1167/iovs.66.13.15","url":null,"abstract":"<p><strong>Purpose: </strong>We previously demonstrated that intravenous pitavastatin Poly (lactic-co-glycolic acid) nanoparticles (PVS-NPs) reduced monocyte/macrophage activation and mitigated cone-cell death in a mouse model of RP. Here, we sought to optimize the PVS-NP administration regimen and investigated underlying molecular mechanisms by single-cell analyses.</p><p><strong>Methods: </strong>In our previous study, twice-weekly administration of 0.3 mg/kg PVS-NPs reduced cone-cell degeneration in rd10 mice with Pde6b mutations. Here, we conducted a dose escalation study with weekly injections of 0.1, 0.3, and 1.0 mg/kg PVS-NPs in rd10 mice, followed by interval optimization with monthly and twice-monthly regimens from postnatal day 21 (P21) to P49. The cone-cell density (primary outcome) and photopic b-wave amplitude (secondary outcome) were assessed at P50. Finally, PVS-NP efficacy was validated in RhoP23H mice with Rhodopsin mutations.</p><p><strong>Results: </strong>Cone densities and photopic b-wave amplitudes were approximately doubled in rd10 mice treated weekly with 0.3 or 1.0 mg/kg PVS-NPs compared with PBS-treated controls. Based on the efficacy of a 1.5 mg/kg cumulative dose in the weekly 0.3 mg/kg group, we evaluated lower dose, reduced frequency regimens: twice monthly 0.5 mg/kg (1.0 mg total) and monthly 0.75 mg/kg (0.75 mg total). The monthly 0.75 mg/kg regimen significantly preserved cone-cell density and function in rd10 mice and RhoP23H mice. Single-cell analyses of rd10 retinas and peripheral blood revealed that PVS-NPs shifted monocytes from a proinflammatory to an anti-inflammatory state and reduced their infiltration into the retina.</p><p><strong>Conclusions: </strong>Monthly intravenous administration of PVS-NPs may be an effective treatment regimen to delay cone-cell degeneration in RP. The therapeutic effect of PVS-NPs likely involves the modulation of circulating inflammatory monocytes and their engraftment.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"15"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Validation of Polygenic Scores for Retinal Vessel Calibers.","authors":"Chenglong Yu, Nuwanthi Rupasinghe, Liubov Robman, Lauren A B Hodgson, Thao Pham, Robyn L Woods, Rory Wolfe, Stephanie A Ward, Walter P Abhayaratna, Robyn H Guymer, Catherine Robb, Peter D Fransquet, Tian Lin, Xueling Sim, Tien Yin Wong, Stuart MacGregor, John J McNeil, Paul Lacaze","doi":"10.1167/iovs.66.13.9","DOIUrl":"https://doi.org/10.1167/iovs.66.13.9","url":null,"abstract":"<p><strong>Purpose: </strong>Retinal vessel calibers are genetically heritable, quantitatively measured, and noninvasive ocular biomarkers of microvascular health. Despite their heritability identified from genome-wide association studies (GWASs), polygenic scores (PGSs) for these traits have not been developed. We aimed to calculate PGSs and associate them with retinal vessel caliber phenotypes in older adults.</p><p><strong>Methods: </strong>Our study included 3717 individuals of European ancestry aged ≥70 years with retinal imaging and genome-wide genotype data. Retinal vessel calibers were measured from fundus photographs and summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). PGSs for each trait were constructed using the SBayesRC method, incorporating prior GWAS summary statistics. Associations between PGSs and measured CRAE and CRVE were examined using linear regression, adjusting for demographic and clinical covariates.</p><p><strong>Results: </strong>Both PGSs were associated with their corresponding retinal vessel calibers. In fully adjusted models, each standard deviation increase in the CRAE and CRVE PGSs was associated with a 1.53 and 3.89 µm increase in vessel diameter, respectively (both P < 0.0001). Fully adjusted models explained 6.0% of CRAE and 7.1% of CRVE variance. A dose-response pattern was observed across increasing PGS quartiles for CRAE and CRVE. Participants in the highest PGS quartile, versus the lowest, had 4.23 µm wider arterioles for CRAE, and 9.50 µm wider venules for CRVE (both P < 0.0001).</p><p><strong>Conclusions: </strong>PGSs for CRAE and CRVE are associated with measured retinal microvascular phenotypes. These findings illustrate the genetic contribution to retinal vessel calibers and provide insights into mechanisms of microvascular and macrovascular health.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"9"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher Throughput Assays for Understanding the Pathogenicity of Variants of Unknown Significance in the RPE65 Gene.","authors":"Leila Azizzadeh Pormehr, Kannan Vrindavan Manian, Ha Eun Cho, T Michael Redmond, Jason Comander","doi":"10.1167/iovs.66.13.10","DOIUrl":"https://doi.org/10.1167/iovs.66.13.10","url":null,"abstract":"<p><strong>Purpose: </strong>RPE65 is a key enzyme in the visual cycle that regenerates 11-cis-retinal. Mutations in RPE65 cause a retinal dystrophy that is treatable with an approved gene therapy. Variants of unknown significance (VUS) on genetic testing can prevent patients from obtaining a firm genetic diagnosis and accessing gene therapy. Because most RPE65 mutations have a low protein expression level, this study developed and validated multiple methods for assessing the expression level of RPE65 variants. This functional evidence is expected to aid in reclassifying RPE65 VUS as pathogenic, which can improve the diagnosis and treatment of RPE65 patients.</p><p><strong>Methods: </strong>Thirty different variants of RPE65 (12 pathogenic, 13 VUS, five benign) were cloned into lentiviral expression vectors. Protein expression levels were measured after transient transfection or in stable cell lines, using western blots and immunostaining with flow cytometry. Then, a pooled, high-throughput, fluorescence-activated cell sorting (FACS) assay with a next-generation sequencing-based readout was used to assay pools of RPE65 variants.</p><p><strong>Results: </strong>A high correlation was observed between protein levels measured by western blot, flow cytometry, and the pooled FACS assay. Using these assays, we confirmed and extended RPE65 variant data, including that Pro111Ser has a low, pathogenic expression level. There was a high correlation between RPE65 expression and previously reported enzyme activity levels; further development of a high-throughput enzymatic activity assay would complement these expression data.</p><p><strong>Conclusions: </strong>This scalable approach can be used to solve patient pedigrees with VUS in RPE65, facilitating treatment and providing RPE65 structure-function information.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"10"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optic Disc Characteristics in Children Born Preterm With and Without ROP: Results From the Gutenberg Prematurity Eye Study Young (GPESY).","authors":"Achim Fieß, Sandra Gißler, Stephanie Grabitz, Eva Mildenberger, Timo Uphaus, Marianne Hahn, Norbert Pfeiffer, Alica Hartmann, Alexander K Schuster","doi":"10.1167/iovs.66.13.21","DOIUrl":"https://doi.org/10.1167/iovs.66.13.21","url":null,"abstract":"<p><strong>Purpose: </strong>We investigated optic nerve head morphology in children born preterm with and without retinopathy of prematurity (ROP), focusing on peripapillary retinal nerve fiber layer (pRNFL) thickness, minimal rim width (MRW), Bruch's membrane opening (BMO), and vertical cup-to-disc ratio (vCDR) in relation to perinatal factors (gestational age [GA], birth weight [BW], perinatal adverse events [PAE]).</p><p><strong>Methods: </strong>This prospective observational cohort included 793 former preterm children aged four to 17 years, stratified into late preterm (GA 33-36 weeks), moderate preterm (GA 29-32 weeks), extreme preterm (GA ≤28 weeks), preterm with untreated ROP, preterm with ROP treatment, and full-term controls (GA ≥37 weeks). Effects of perinatal factors on pRNFL, MRW, BMO area, and vCDR were evaluated.</p><p><strong>Results: </strong>Extremely preterm children had a thinner pRNFL (β = -9.25, P < 0.001), except temporally. ROP-treated children showed thicker temporal (β = 43.31, P < 0.001) and inferotemporal (β = 20.97, P = 0.04) pRNFL but thinner superonasal sectors. PAE (β = -7.68, P < 0.001) and maternal smoking (temporal β = -12.02, P = 0.003) were associated with thinner pRNFL, whereas breastfeeding was linked to thicker pRNFL (β = 2.25, P = 0.003). MRW was thinner in extremely preterm infants, particularly inferiorly (inferotemporal β = -30.36, inferonasal β = -28.85, all P ≤ 0.02). VCDR was larger in extreme (β = 0.05, P = 0.001) and moderate (β = 0.04, P = 0.004) preterms. BMO area showed no associations.</p><p><strong>Conclusions: </strong>Prematurity was associated with thinner pRNFL, smaller MRW, and larger vCDR. ROP treatment was linked to thicker temporal pRNFL and thicker MRW. PAE and maternal smoking were associated with thinner pRNFL, whereas breastfeeding correlated with greater thickness.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"21"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of Photoreceptor Synaptic Ribbons in the Retina of a Human Patient With Oculocutaneous Albinism Type 1 (OCA1).","authors":"Anna Franziska Köller, Barbara Käsmann-Kellner, Fritz Benseler, Thomas Tschernig, Ursula Löw, Stephan Maxeiner, Karin Schwarz, Nils Brose, Gerd Geerling, Berthold Seitz, Frank Schmitz","doi":"10.1167/iovs.66.13.14","DOIUrl":"https://doi.org/10.1167/iovs.66.13.14","url":null,"abstract":"<p><strong>Purpose: </strong>Albino (Tyrc-2J/Tyrc-2J) C57BL/6J mice carry a mutation in the tyrosinase gene and are known to display alterations of photoreceptor synaptic ribbons. In the present study, we wanted to test whether similar alterations exist in oculocutaneous albinism type 1 (OCA1), a human disease that also results from mutations in the tyrosinase gene.</p><p><strong>Methods: </strong>In the present study, we assessed the morphology of a human OCA1 retina in comparison to control human retinas. We analyzed the retina of a 35-year-old OCA1 patient by immunolabeling at light and electron microscopic levels, conventional transmission electron microscopy, and by genomic DNA sequencing of the RIBEYE/CtBP2 gene in comparison to normal human controls.</p><p><strong>Results: </strong>The morphological analyses revealed an overall surprisingly normal appearance of the retina, except for the presence of strikingly abnormal photoreceptor synaptic ribbons. Synaptic ribbons are presynaptic specializations of the continuously active retinal ribbon synapses and mainly consist of the RIBEYE protein. In the OCA1 patient, photoreceptor synaptic ribbons were very small and reduced to small fragments that were either still associated with the active zone transmitter release site or floating in the cytosol. The RIBEYE gene appeared to be unaltered in the OCA1 patient, except for some single nucleotide polymorphisms (SNPs) that were also present in controls.</p><p><strong>Conclusions: </strong>The OCA1 patients displayed similar defects of photoreceptor synaptic ribbons as previously observed in the albinotic mice with a defect in the tyrosinase gene. The observed alterations of synaptic ribbons are not due to mutations in the RIBEYE gene but are likely indirect consequences of the deficient melanin biosynthesis in the OCA1 patient.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"14"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of Visual Motion Signals in Reduced Visual Conditions.","authors":"Xi Wang, Tong Liu, Changwu Tan, Yutong Song, Longqian Liu, Alexandre Reynaud","doi":"10.1167/iovs.66.13.18","DOIUrl":"https://doi.org/10.1167/iovs.66.13.18","url":null,"abstract":"<p><strong>Purpose: </strong>Neural sensory systems continuously tailor themselves to adapt to changes in the surrounding environment. In motion adaptation, a certain period of exposure to consistent motion in one direction (inducer) will alter the perceived direction of motion of the following stimulus. Depending on the timescale of the inducer, two opposite adaptation phenomena can be observed: motion priming for brief inducers, and motion aftereffect for longer inducers. The aim of this study was to investigate how the integration of motion signals during adaptation is affected by externally reduced visual conditions, such as luminance, contrast, and spatial frequency. We then considered how this would apply to the naturally impaired visual system in amblyopia.</p><p><strong>Methods: </strong>We addressed this question by taking advantage of a visual illusion, the High-phi illusion. We measured the High-phi transition point when manipulating the visual conditions (contrast and luminance), the targeted subpopulations of neurons (by varying spatial frequency), and the integration properties of the visual system by changing the viewing conditions (monocular viewing, binocular viewing, and testing amblyopic participants).</p><p><strong>Results: </strong>We found a larger transition point under high spatial frequency, low luminance, low contrast, and monocular viewing conditions. We then propose a model of temporal integration, for the motion signals, that accurately describes those effects.</p><p><strong>Conclusions: </strong>Finally, we validated our model by testing amblyopic participants and demonstrating that the amblyopic visual system exhibits a larger High-phi transition point, thereby characterizing slower temporal integration. Overall, our results show that the integration of visual motion energy could switch adaptation from priming to aftereffect.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"18"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Transcription Factor Islet-1 Regulates Diabetes-Induced Inner Blood-Retinal Barrier Disruption.","authors":"Nan Wang, Fei Yao, Wenji Xu, Tianxu Feng, Zhenyu Li, Quyan Zhang, Wanpeng Wang, Xueyong Zhang, Wenbo Lei, Guoli Zheng, Yao Xu, Die Liu, Yiming Zhu, Xiaobo Xia, Siqi Xiong","doi":"10.1167/iovs.66.13.8","DOIUrl":"10.1167/iovs.66.13.8","url":null,"abstract":"<p><strong>Purpose: </strong>The transcription factor Islet-1 (Insulin gene enhancer protein Isl-1) has been implicated in diabetic retinal neovascularization, but its role in inner blood-retinal barrier (iBRB) dysfunction in diabetic retinopathy remains unclear. This study aimed to elucidate the mechanisms by which Islet-1 drives iBRB disruption under diabetic conditions by integrating analyses of clinical samples from patients with diabetic retinopathy, in vivo studies in diabetic mouse models, and in vitro experiments using hyperglycemia-exposed human retinal microvascular endothelial cells.</p><p><strong>Methods: </strong>The expression profile of Islet-1 in diabetic patients and experimental diabetic models were investigated by immunofluorescence staining, Western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Through the modulation of Islet-1 expression, we evaluated its impact on iBRB integrity under diabetic conditions and explored the molecular pathways involved in iBRB disruption.</p><p><strong>Results: </strong>Our findings demonstrated that elevated Islet-1 expression correlates with the progression of diabetic retinopathy and the breakdown of the iBRB. Mechanistically, Islet-1 upregulation led to increased vascular endothelial growth factor A (VEGFA) expression and decreased levels of key tight junction proteins Occludin and Zonula occludens-1 (ZO-1) in retinal vascular endothelial cells.</p><p><strong>Conclusions: </strong>Our results establish Islet-1 as a critical regulator of iBRB disruption in diabetic retinopathy and suggest that targeting Islet-1 overexpression may represent a novel therapeutic approach to mitigate iBRB dysfunction and its associated retinal pathologies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"8"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Vagal Tone Function-Based Regulation of Systemic Inflammation in Patients With Neovascular Age-Related Macular Degeneration.","authors":"Christopher R Molbech, Marie-Louise Munch Bøegh, Marie Krogh Nielsen, Yousif Subhi, Charlotte Liisborg, Christophe Roubeix, Florian Sennlaub, Jesper Mehlsen, Torben L Sørensen","doi":"10.1167/iovs.66.13.16","DOIUrl":"https://doi.org/10.1167/iovs.66.13.16","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to investigate vagal nerve function and correlation to CD4+ T-cell population in patients with neovascular age-related macular degeneration (nvAMD) and healthy individuals.</p><p><strong>Methods: </strong>This study is a prospective case-control study including 36 patients with nvAMD and 40 healthy individuals. We measured the proxy of vagus nerve activity, the resting heart rate variability (HRV). Freshly sampled venous blood was prepared to measure CD4+ T-cell populations regulated by the vagal tone (regulatory T cells [Tregs], recently thymic emigrant Tregs, naïve Tregs, and effector memory T cells).</p><p><strong>Results: </strong>Compared with healthy individuals, patients with nvAMD had significantly lower HRV (low frequency/high frequency [LF/HR] ratio, P = 0.037 and standard deviation [SD] ratio, P = 0.011), indicating impaired vagal function. HRV measures negatively correlated to the proportion of Tregs (square root of the mean squared difference of successive NN intervals [RMSSD], P = 0.046) and memory T cells (RMSSD, P = 0.046) in healthy individuals, suggesting an intact regulatory capacity. These correlations were not found in patients with neovascular AMD, suggesting an impaired vagus nerve-regulatory T cell axis. Patients with nvAMD had significantly higher Tregs (P = 0.0005), naïve Tregs (P = 0.016), and recent thymic emigrant Tregs (P = 0.015).</p><p><strong>Conclusions: </strong>Vagal tone is impaired in patients with nvAMD which disharmonizes with increased Tregs in the systemic circulation. These altered regulators may be the key to increased systemic inflammation, present in patients with nvAMD.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"16"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging Affects Lipid Homeostasis in Lacrimal Glands by Upregulating Lipogenesis and Changing Its Specificity.","authors":"Seher Yuksel, Prashant Kumar, Sydney E Krenz, Kaitlin K Scholand, Zhiyuan Yu, Anastasiia Ivanova, Helen P Makarenkova, Sarah F Hamm-Alvarez, Igor A Butovich, Cintia S de Paiva","doi":"10.1167/iovs.66.13.1","DOIUrl":"10.1167/iovs.66.13.1","url":null,"abstract":"<p><strong>Purpose: </strong>The lacrimal gland (LG) develops age-related alterations. This study investigated the lipid content of the accumulated secretions within the murine aged LG.</p><p><strong>Methods: </strong>C57BL/6J animals of different ages (3 months, 12 months, and 20-26 months) were used. Published data of bulk RNA sequencing of aged LGs were used to investigate lipid pathways. Exorbital LGs were excised for histology or PCR. Histologic sections were stained with standard histochemical stains or immunostained using anti-adiponectin, anti-perilipin 2 antibodies, and BODIPY dye. LG lipidomes were investigated using unbiased, untargeted high-resolution liquid chromatography/mass spectrometry (LC/MS), and the data were processed using unbiased, untargeted principal component and orthogonal projections to latent structure discriminant analyses.</p><p><strong>Results: </strong>Analyses of aged LGs revealed distinct changes in their state: immune infiltration without and with large dilated epithelial ducts. Sudan black and Oil Red O staining of cystic LG sections demonstrated lipid accumulation within the dilated epithelial ducts, accompanied by lymphocytic infiltration around dilated ductal structures. Bulk RNA sequencing of glands indicated upregulated transcription of genes associated with lipid metabolism, fatty acid synthesis, and lipid droplet formation. Adiponectin protein expression was restricted to ducts. Immunoreactivity to perilipin 2 and BODIPY was only observed in aged epithelial ducts. Moreover, lipidomic LC/MS analysis revealed a significant increase in the total lipid content in aged LGs compared to young LGs, with a pronounced accumulation in the neutral lipid fraction, particularly triglycerides.</p><p><strong>Conclusions: </strong>The changes in LG lipidomes of aging mice indicate a considerable age-related shift in the specificity and efficacy of lipogenesis in LG.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"1"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgene-Induced Chromosomal Rearrangement With Aberrant Human Vascular Endothelial Growth Factor at the Optic Fissure Leads to Uveal Coloboma in Mice.","authors":"Yuhong Anna Wang, Ramakrishna P Alur, Vijay Kalaskar, Aman George, Elangovan Boobalan, David M McGaughey, Felix I Onojafe, Amalia Dutra, Evgenia Pak, James W Thomas, Lijin Dong, Marcus Fruttiger, Sandra Pieke-Dahl, Bin Guan, Peter F Hitchcock, Brian P Brooks","doi":"10.1167/iovs.66.13.7","DOIUrl":"10.1167/iovs.66.13.7","url":null,"abstract":"<p><strong>Purpose: </strong>The pathogenesis of uveal coloboma, a potentially blinding congenital ocular malformation, is incompletely understood. We characterize a novel mouse model of coloboma, Retinal and Iris Coloboma (RICO).</p><p><strong>Methods: </strong>Transgenic mice were created by insertion of a human vascular endothelial growth factor-165 (hVEGF) gene driven by a neuron-specific enolase promoter. Mice were examined clinically and histologically, and the insertion site was characterized by fluorescence in situ hybridization and genomic sequencing. Gene expression changes were assessed with RNA sequencing, immunofluorescence, and in situ hybridization.</p><p><strong>Results: </strong>RICO mice are viable in the homozygous state and exhibit fully penetrant autosomal semidominant coloboma. Coloboma is associated with persistence of periocular mesenchyme in the optic fissure, likely contingent on a specific, transgene insertion-induced genomic rearrangement on chromosome 13 that drives aberrant hVEGF expression. RICO eye cups exhibit altered expression of genes in the vicinity of the insertion site, where deletions of the human homologous locus were found in coloboma patients. RNA sequencing demonstrates changes in multiple coloboma-associated genes.</p><p><strong>Conclusions: </strong>RICO represents a useful model for studying the pathogenesis of human coloboma.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 13","pages":"7"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}