Proximity interactions of Frizzled4 (FZD4) in the bEnd.3 mouse brain endothelial cell line
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Cell Culture, Endothelial Cell
SUBMITTER: 
Kevin Murray
LAB HEAD: Harald Junge
PROVIDER: PXD077093 | Pride | 2026-04-14
REPOSITORIES: Pride
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Project description:Introduction: Retinopathy of prematurity (ROP) with early vessel loss (Phase I) followed by uncontrolled vessel growth (Phase II) causes visual impairment in premature infants. Although supplementation with n-3 docosahexaenoic acid (DHA) alone has mixed results to prevent ROP, combined supplementation with DHA and n-6 arachidonic acid (ARA) in early postnatal life reduces severe ROP by 50% (Mega Donna Mega study). The underlying mechanisms are unknown. Objectives: To evaluate protective effects and mechanism of combined dietary n-3 DHA and n-6 ARA in a neonatal mouse model of Phase I ROP. Methods: In the Mega Donna Mega study, most preterm infants had early postnatal hyperglycemia episodes, a strong risk factor for severe ROP. We used a neonatal mouse model of hyperglycemia-induced suppression of retinal vascular development (Phase I ROP). Dams were fed diets enriched with 3%DHA or 1%DHA+2%ARA. In P10 milk-fed pups, we assessed retinal vascularization, and proteome, and fatty acid profiles in retina, retinal pigment epithelium (RPE) complex and plasma. In vivo, oligomycin A, a mitochondrial ATP synthase inhibitor, was used to assess mitochondrial participation in the combined lipid protective effects. Results: In 201 (97.6%) of 206 randomized infants there was at least one elevated glucose measurement during the first 14 days. In a neonatal mouse model of hyperglycemia-induced suppression of vascular development, maternal DHA+ARA vs. DHA diet promoted pup retinal vessel growth. Fatty acid profiling confirmed lipid changes in pup plasma and RPE complex in accord with DHA and ARA levels in the maternal diets. Proteomic retinal analysis revealed increased abundance of proteins related to mitochondrial respiration and glucose metabolism in the combined diet. Inhibition of mitochondrial ATP synthase negated the protective effects of the combined diet on retinal vascularization. Conclusion: Combined DHA+ARA oral supplementation in the early postnatal period protects against Phase I ROP in mouse neonates, through enhanced retinal metabolism suggesting the potential of balanced lipid supplementation for preventing ROP.
2025-09-29 | PXD061307 | Pride
Project description:Pathological retinal angiogenesis with irregular and fragile vessels (also termed as neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups driven in part by unmet metabolic demand from retinal neurons. Sustaining neural retinal metabolism with an adequate nutrient supply may prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism is suggested in retinopathy of prematurity. Here we assessed the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization in mice. Systemic serine supplementation decreased, and dietary serine/glycine deficiency worsened retinal neovascularization. Fatty acid oxidation was essential in mediating serine protective effects and serine also increased the levels of phosphatidylcholine, the most abundant phospholipids in the retina. Exogenous serine increased abundance of proteins involved in oxidative phosphorylation in total retinas, as well as increased expression of mitochondrial respiration-related genes and decreased expression of pro-angiogenic genes in rod photoreceptor cluster. Pharmaceutical inhibition of mitochondrial energy production largely attenuated serine suppression of retinal neovascularization. Our data suggested that increasing serine is a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial function and lipid metabolism to suppress driving factors for uncontrolled angiogenesis.
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Project description:Alzheimer's Disease (AD) and Non-Demented Control (NDC) human sera were probed onto human protein microarrays in order to identify differentially expressed autoantibody biomarkers that could be used as diagnostic indicators. In the study presented here, 50 AD and 40 NDC human serum samples were probed onto human protein microarrays in order to identify differentially expressed autoantibodies. Microarray data was analyzed using several statistical significance algorithms, and autoantibodies that demonstrated significant group prevelance were selected as biomarkers of disease. Prediction classification analysis tested the diagnostic efficacy of the identified biomarkers; and differentiation of AD samples from other neurodegeneratively-diseased and non-neurodegeneratively-diseased controls (Parkinson's disease and breast cancer, respectively) confirmed their specificity.
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Project description:Background: Dyslipidemia is a significant contributor to many eye diseases and the lipid processing pathways are not well understood. Peroxisomes oxidize very long-chain, monocarboxylic and dicarboxylic fatty acids. Genetic mutations in peroxisomal proteins may lead to severe neural retinal degeneration. However, there are limited approaches available for peroxisomal disease treatment. Method: In mice with genetic deficiency of ACOX1 (acyl-coenzyme A oxidase 1, the first and key metabolic enzyme in peroxisomal fatty acid oxidation), we characterized the retinal phenotype during development. Retinal function, thickness and photoreceptor structure were examined. Proteomics was utilized for molecular mechanistic investigation. Metabolomics and fatty acid profiling and were conducted to study the metabolic alterations in the retinas. Nutrient intervention was also applied to test if supplementation of lacking nutrients attenuated retinal dysfunction. Results: In one-month-old mice with ACOX1 deficiency, we found reduced neural retinal signaling, accompanied with decrease expression of genes involved in phototransduction. Proteomics identified decreased glucose and mitochondrial metabolism, supported by decreased mitochondrial DNA copy number. Metabolomics showed decreased retinal pyruvate and pyruvate supplementation from one-month old attenuated neural retinal dysfunction in ACOX1-deficient mice at 2 months. Furthermore, there was also a significant decrease in omega-3 fatty acids and a compensatory increase in omega-6 fatty acids. Dietary supplementation of docosahexaenoic acid (omega-3) or docosahexaenoic acid plus arachidonic acid (omega-6) improved neural retinal function in ACOX1-deficient mice. Conclusion: Retinal metabolic imbalance was observed in mice with peroxisomal fatty acid dysfunction. Nutrient intervention is an effective approach to attenuate the disease progression.
2025-12-15 | PXD055240 | Pride
Project description:Although-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with -synuclein triplication or controls where endogenous -synuclein was imprinted into synthetic or disease-relevant conformations. We used -synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in -synuclein levels in -synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in -synuclein gene expression. Progressive neuronal loss was observed only in -synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of -synuclein triplication revealed that intraneuronal-synuclein levels solely and sufficiently explained vulnerability to neuronal death. Proximity-dependent biotinylation in living cells identified 56 differentially interacting proteins with endogenously assembled -synuclein including evasion of Parkinson’s disease-associated deglycase DJ-1 by aggregates triggered with brain amplified fibrils. Knockout of DJ-1 and related glyoxalase-1 in cell lines increased -synuclein aggregation. Similarly, methylglyoxal treatment or CRISPR/Cas9 knockout of DJ-1 in iPSC-derived dopaminergic neurons enhanced fibril-induced aggregation and cell death. Thus, toxicity of -synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our results define parameters for iPSC-based modellingof -synuclein pathology using brain amplified fibrils and demonstrate how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.
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Project description:Fewer than 50% of patients develop vascular and valvular calcification, implying differential pathogenesis. Disease stage-specific proteomics (non-diseased/fibrotic/calcified areas) was performed on human carotid endarterectomy specimens and stenotic aortic valves merged per donor as fractions.
2023-07-10 | PXD035563 | Pride
Project description:Parkinson's Disease (PD) and Non-Demented Control (NDC) human sera were probed onto human protein microarrays in order to identify differentially expressed autoantibody biomarkers that could be used as diagnostic indicators. In the study presented here, 29 PD and 40 NDC human serum samples were probed onto human protein microarrays in order to identify differentially expressed autoantibodies. Microarray data was analyzed using several statistical significance algorithms, and autoantibodies that demonstrated significant group prevelance were selected as biomarkers of disease. Prediction classification analysis tested the diagnostic efficacy of the identified biomarkers; and differentiation of PD samples from other neurodegeneratively-diseased and non-neurodegeneratively-diseased controls (Alzheimer's disease, multiple sclerosis, and breast cancer) confirmed their specificity.
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Project description:Background: Calcific aortic valve disease (CAVD), the most common valve disease is comprised of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. Methods: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14 and 21 days; and processed for imaging, proteomics, transcriptomics and single-cell RNA sequencing (scRNA-seq). Results: The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice versus littermate controls. We identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin and p-38 MAPK signaling. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6 and SAA1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. Conclusions: Sortilin promotes experimental CAVD by mediating valvular fibrosis and calcification, and newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in aortic valve calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.
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2023-07-10 | PXD035538 | Pride