Flexible DPPT-TT/PEO Fiber-Exploiting Electro-optical Synaptic Transistor for Artificial Withdrawal Reflex Arc

Advanced Fiber Materials, Journal Year: 2024, Volume and Issue: 6(2), P. 401 - 413

Published: Jan. 10, 2024

Language: Английский

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Multiomics analyses reveal early metabolic imbalance and mitochondrial stress in neonatal photoreceptors leading to cell death in Pde6brd1/rd1 mouse model of retinal degeneration

Human Molecular Genetics, Journal Year: 2022, Volume and Issue: 31(13), P. 2137 - 2154

Published: Jan. 11, 2022

Abstract Retinal diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset severity. Mutations in over 200 genes can lead to photoreceptor dysfunction and/or cell death retinal neurodegeneration. To deduce molecular pathways that initiate drive death, we adopted a temporal multiomics approach examined cellular events newborn developing photoreceptors before the of degeneration widely-used Pde6brd1/rd1 (rd1) mouse, model autosomal recessive retinitis pigmentosa caused by PDE6B mutations. Transcriptome profiling neonatal rods from rd1 retina revealed early downregulation associated anabolic energy metabolism. Quantitative proteomics showed changes calcium signaling oxidative phosphorylation, specific partial bypass I electron transfer, which precede death. Concurrently, detected alterations central carbon metabolism, including dysregulation components glycolysis, pentose phosphate purine biosynthesis. Ex vivo assays oxygen consumption transmission microscopy validated progressive mitochondrial stress abnormalities structure function rods. These data uncover overactivation related metabolic as determinants pathology implicate aberrant an initiator higher stress. Our studies thus provide mechanistic framework damage disruptions drivers degeneration.

Language: Английский

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One-stop assembly of adherent 3D retinal organoids from hiPSCs based on 3D-printed derived PDMS microwell platform

Biofabrication, Journal Year: 2023, Volume and Issue: 15(3), P. 035005 - 035005

Published: March 24, 2023

Abstract The three-dimensional (3D) retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs), mimicking the growth and development of retina, is a promising model for investigating inherited diseases in vitro . However, efficient generation homogenous ROs remains challenge. Here we introduce novel polydimethylsiloxane (PDMS) microwell platform containing 62 V-bottom micro-cavities differentiation hiPSCs. uniform adherent 3D could spontaneously form using neural retina (NR) induction. Our results showed that complex NR (expressing VSX2), ciliary margin (CM) RDH10), pigment epithelium (RPE) ZO-1, MITF, RPE65) developed PDMS after differentiation. It important to note platforms not only enable one-stop assembly but also maintain homogeneity mature over period more than 25 weeks without use BMP4 Matrigel. Retinal ganglion BRN3a), amacrine AP2a), horizontal PROX1 AP2 α ), photoreceptor cone S-opsin L/M-opsin) rod Rod opsin), bipolar VSX2 PKC Müller glial GS Sox9) gradually emerged. Furthermore, replaced fetal bovine serum with platelet lysate established xeno-free culture workflow facilitates clinical application. Thus, our long-term favorable disease modeling, drug screening, manufacturing translation.

Language: Английский

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Genetic context modulates aging and degeneration in the murine retina

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 20, 2025

Abstract Background Age is the principal risk factor for neurodegeneration in both retina and brain. The brain share many biological properties; thus, insights into retinal aging degeneration may shed light onto similar processes Genetic makeup strongly influences susceptibility to age-related disease. However, studies investigating have not sufficiently accounted genetic diversity. Therefore, examining molecular across different backgrounds will enhance our understanding of human-relevant brain—potentially improving therapeutic approaches these debilitating conditions. Methods Transcriptomics proteomics were employed elucidate signatures nine genetically diverse mouse strains (C57BL/6J, 129S1/SvlmJ, NZO/HlLtJ, WSB/EiJ, CAST/EiJ, PWK/PhK, NOD/ShiLtJ, A/J, BALB/cJ) lifespan. These data predicted human disease-relevant changes WSB NZO strains. Accordingly, B6, WSB, mice subjected vivo examinations at 4, 8, 12, and/or 18M, including: slit lamp, fundus imaging, optical coherence tomography, fluorescein angiography, pattern/full-field electroretinography. Retinal morphology, vascular structure, cell counts assessed ex . Results We identified common strains, which included genes associated with photoreceptor function immune activation. background modulated signatures. Analysis type-specific marker loss photoreceptors ganglion cells (RGCs) NZO, respectively. Fundus exams revealed retinitis pigmentosa-relevant pigmentary abnormalities retinas diabetic retinopathy (DR)-relevant cotton wool spots exudates retinas. Profound dysfunction confirmed WSB. Molecular analyses indicated photoreceptor-specific proteins prior loss, suggesting photoreceptor-intrinsic In addition, age-associated RGC dysfunction, concomitant microvascular observed mice. Proteomic an early reduction protective antioxidant processes, underlie increased DR-relevant pathology NZO. Conclusions context a strong determinant aging, multi-omics resource can aid diseases eye Our investigations validated as improved preclinical models relevant neurodegenerative diseases.

Language: Английский

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Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

Journal of Lipid Research, Journal Year: 2020, Volume and Issue: 62, P. 100057 - 100057

Published: Oct. 20, 2020

Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails interplay between de novo synthesis, uptake, intraretinal sterol transport, metabolism, efflux. Defects in these complex processes are associated with several congenital age-related disorders visual system. Herein, we provide an overview following topics: (a) synthesis neural retina; (b) lipoprotein uptake transport retina retinal pigment epithelium (RPE); (c) efflux from RPE; (d) biology pathobiology defects oxidation RPE. We focus, particular, on studies involving animal models monogenic pertinent to above topics, as well vitro using biochemical, metabolic, omic approaches. also identify current knowledge gaps opportunities field beg further research this topic area.

Language: Английский

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Age‐related dysregulation of the retinal transcriptome in African turquoise killifish

Aging Cell, Journal Year: 2024, Volume and Issue: 23(8)

Published: May 14, 2024

Abstract Age‐related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of on homeostasis, we used short‐lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) hallmarks loss. Bulk single‐cell RNA‐sequencing (scRNAseq) three age groups (6‐, 12‐, 18‐week‐old) identified transcriptional fingerprints killifish retina, unveiling pathways also aged brain, including oxidative stress, gliosis, inflammageing. These findings were comparable observations mouse retina. Additionally, changes genes related diseases, such as glaucoma age‐related macular degeneration, observed. The cellular heterogeneity retina was characterized, confirming presence all typical vertebrate cell types. Data integration from age‐matched samples between bulk scRNAseq experiments revealed specificity gene expression upon ageing, suggesting potential disruption homeostasis. Differential analysis within types highlighted role glial/immune cells important stress regulators during ageing. Our work emphasizes value fast‐ageing elucidating signatures age‐associated disease decline. This study contributes understanding how may CNS health, providing insights that inform future therapeutic strategies for pathologies.

Language: Английский

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Photoreceptor phosphodiesterase (PDE6): activation and inactivation mechanisms during visual transduction in rods and cones

Pflügers Archiv - European Journal of Physiology, Journal Year: 2021, Volume and Issue: 473(9), P. 1377 - 1391

Published: April 15, 2021

Language: Английский

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The temporal progression of retinal degeneration and early-stage idebenone treatment in the Pde6brd1/rd1 mouse model of retinal dystrophy

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 23, 2024

Abstract Photoreceptor cell death, primarily through apoptosis, related to retinal disorders like retinitis pigmentosa (RP), would result in vision loss. The pathological processes and crucial mutant conditions preceding photoreceptor demise are not well understood. This study aims conduct an in-depth examination of early-stage changes the widely utilized Pde6b rd1/rd1 (rd1) mouse model, which has gene mutations representing autosomal recessive RP disorder. We investigated morphology ultrastructure cells, including second-order neurons, during initial phase disease progression. Our findings revealed that mitochondrial alterations rod photoreceptors were present as a predeath state early postnatal day 3 (P3). bipolar horizontal cells from rd1 retina exhibited significant morphological response loss indicating neurons rely on these for their structures. Subsequent oral administration idebenone, mitochondria-protective agent, enhanced function promoted both survival inner synaptogenesis mice at P14. offer mechanistic framework, suggesting damage acts driver death degeneration.

Language: Английский

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PCYT1A deficiency disturbs fatty acid metabolism and induces ferroptosis in the mouse retina

BMC Biology, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 10, 2024

Language: Английский

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Sustained Inhibition of NF-κB Activity Mitigates Retinal Vasculopathy in Diabetes

American Journal Of Pathology, Journal Year: 2021, Volume and Issue: 191(5), P. 947 - 964

Published: Feb. 26, 2021

Language: Английский

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