Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region.
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ABSTRACT:
SUBMITTER: Junnuthula V
PROVIDER: S-EPMC8066548 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and in human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and on separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix-receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
| S-EPMC10054954 | biostudies-literature
Project description:The glial protein S100B, which belongs to a calcium binding protein family, is up-regulated in neurological diseases, like multiple sclerosis or glaucoma. In previous studies, S100B immunization led to retinal ganglion cell (RGC) loss in an experimental autoimmune glaucoma (EAG) model. Now, the direct degenerative impact of S100B on the retina and optic nerve was evaluated. Therefore, 2 ?l of S100B was intravitreally injected in two concentrations (0.2 and 0.5 ?g/?l). At day 3, 14 and 21, retinal neurons, such as RGCs, amacrine and bipolar cells, as well as apoptotic mechanisms were analyzed. Furthermore, neurofilaments, myelin fibers and axons of optic nerves were evaluated. In addition, retinal function and immunoglobulin G (IgG) level in the serum were measured. At day 3, RGCs were unaffected in the S100B groups, when compared to the PBS group. Later, at days 14 and 21, the RGC number as well as the ?-III tubulin protein level was reduced in the S100B groups. Only at day 14, active apoptotic mechanisms were noted. The number of amacrine cells was first affected at day 21, while the bipolar cell amount remained comparable to the PBS group. Also, the optic nerve neurofilament structure was damaged from day 3 on. At day 14, numerous swollen axons were observed. The intraocular injection of S100B is a new model for a glaucoma like degeneration. Although the application site was the eye, the optic nerve degenerated first, already at day 3. From day 14 on, retinal damage and loss of function was noted. The RGCs in the middle part of the retina were first affected. At day 21, the damage expanded and RGCs had degenerated in all areas of the retina as well as amacrine cells. Furthermore, elevated IgG levels in the serum were measured at day 21, which could be a sign of a late and S100B independet immune response. In summary, S100B had a direct destroying impact on the axons of the optic nerve. The damage of the retinal cell bodies seems to be a consequence of this axon loss.
| S-EPMC6169322 | biostudies-literature
Project description:Optic nerve head (ONH) and retina (RET) are the main sites of damage in neurodegenerative optic neuropathies including glaucoma. Up to date, little is known about the molecular interplay between these two adjoining ocular components in terms of proteomics. To close this gap, we investigated ONH and RET protein extracts derived from porcine eyes (n = 12) (Sus scrofa domestica Linnaeus 1758) using semi-quantitative mass spectrometry (MS)-based proteomics comprising bottom-up LC-ESI MS/MS and targeted SPE-MALDI-TOF MS analysis. In summary, more than 1600 proteins could be identified from the ONH/RET tissue complex. Moreover, ONH and RET displayed tissue-specific characteristics regarding their qualitative and semi-quantitative protein compositions. Gene ontology (GO)-based functional and protein-protein interaction analyses supported a close functional connection between the metabolic-related RET and the structural-associated ONH subproteomes, which could be affected under disease conditions. Inferred from the MS findings, stress-associated proteins including clusterin, ceruloplasmin, and endoplasmin can be proposed as extracellular mediators of the ONH/ RET proteome interface. In conclusion, ONH and RET show obvious proteomic differences reflecting characteristic functional features which have to be considered for future protein biomarker profiling studies.
| S-EPMC6747248 | biostudies-literature
Project description:PurposeIn this study, we aimed to compare blood flow changes in the optic nerve head (ONH) during horizontal ocular duction among normal, primary open-angle glaucoma (POAG), and normal-tension glaucoma (NTG) eyes.MethodsIn this cross-sectional study, we included 90 eyes from 90 participants (30 control eyes, 30 POAG eyes, and 30 NTG eyes). ONH blood flow was measured with laser speckle flowgraphy using an external fixation light to induce central gaze, abduction, and adduction at 30 degrees for each eye. The mean blur rate (MBR) of the entire ONH area (MA), vascular region (MV), and tissue region (MT), and the change ratio were analyzed. The change ratio was defined as abduction or adduction value/central gaze value.ResultsIn the control group, MA significantly decreased during adduction (22.9 ± 3.7) compared with that during central gaze (23.6 ± 3.9, P < 0.05). In the POAG group, MA (adduction = 17.4 ± 3.8 and abduction = 17.3 ± 3.6) and MV (adduction = 37.9 ± 5.6 and abduction = 38.0 ± 5.6) significantly decreased during adduction and abduction compared with those during central gaze (18.0 ± 4.1 and 39.5 ± 6.3, respectively, P < 0.05). In the NTG group, MA significantly decreased during adduction (17.4 ± 4.2) compared with that during central gaze (18.1 ± 4.6) and abduction (18.1 ± 4.8, P < 0.05). The change ratio did not differ between the glaucoma and control groups.ConclusionsONH blood flow decreased during horizontal ocular duction regardless of normal or glaucoma states; however, the change ratio was comparable between the normal and glaucoma groups.
| S-EPMC10768701 | biostudies-literature
Project description:A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and in human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and on separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix–receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes present three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
2023-09-06 | GSE241782 | GEO
Project description:Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage-specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type-specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.
| S-EPMC7282894 | biostudies-literature
Project description:Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage–specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type–specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.
2020-04-07 | GSE110019 | GEO
Project description:The Pax2 transcription factor plays a crucial role in axon-guidance and astrocyte differentiation in the optic nerve head (ONH) during vertebrate visual system development. However, little is known about its function during regeneration. The fish visual system is in continuous growth and can regenerate. Müller cells and astrocytes of the retina and ONH play an important role in these processes. We demonstrate that pax2a in goldfish is highly conserved and at least two pax2a transcripts are expressed in the optic nerve. Moreover, we show two different astrocyte populations in goldfish: Pax2(+) astrocytes located in the ONH and S100(+) astrocytes distributed throughout the retina and the ONH. After peripheral growth zone (PGZ) cryolesion, both Pax2(+) and S100(+) astrocytes have different responses. At 7 days after injury the number of Pax2(+) cells is reduced and coincides with the absence of young axons. In contrast, there is an increase of S100(+) astrocytes in the retina surrounding the ONH and S100(+) processes in the ONH. At 15 days post injury, the PGZ starts to regenerate and the number of S100(+) astrocytes increases in this region. Moreover, the regenerating axons reach the ONH and the pax2a gene expression levels and the number of Pax2(+) cells increase. At the same time, S100(+)/GFAP(+)/GS(+) astrocytes located in the posterior ONH react strongly. In the course of the regeneration, Müller cell vitreal processes surrounding the ONH are primarily disorganized and later increase in number. During the whole regenerative process we detect a source of Pax2(+)/PCNA(+) astrocytes surrounding the posterior ONH. We demonstrate that pax2a expression and the Pax2(+) astrocyte population in the ONH are modified during the PGZ regeneration, suggesting that they could play an important role in this process.
| S-EPMC3288081 | biostudies-literature
Project description:PurposeTo study effects of age and horizontal duction on deformation of the optic nerve head (ONH) and peripapillary retina (PPR), as reflected by displacement of vascular landmarks, to explore the influence of adduction tethering.DesignCross-sectional study.MethodsSetting: University.Study populationSingle eyes of 20 healthy young adults (average age 23.9 ± 3.9 [SD] years) were compared to 20 older subjects (average age 61.4 ± 9.3 years). Observational Procedure: The disc and PPR were imaged by scanning laser ophthalmoscopy in central gaze and at 35 degrees abduction and adduction.Main outcome measureDeformations of the disc and adjacent PPR were measured by comparing positions of epipapillary and epiretinal blood vessels.ResultsVessels within the ONH of younger subjects shifted temporally during adduction and nasally during abduction. Displacement of the nasal hemi-disc in adduction was greater at 38.5 ± 1.7 μm (standard error of mean) than the temporal half at 4.1 ± 2.1 μm (P < .001). PPR within 1 radius of the disc margin underwent 7.6 ± 1.6 μm average temporal displacement in adduction in young subjects. In abduction, the young temporal hemi-disc shifted 4.4 ± 0.6 μm nasally without significant displacement in the nasal half. Older subjects' ONH showed less temporal shift and less displacement in the PPR within 1 disc radius (P < .0001) in adduction; the nasal hemi-disc shifted 24.5 ± 1.3 μm compared with 4.4 ± 2.1 μm in the temporal half. There were no significant deformations of the disc during abduction by older subjects.ConclusionLarge horizontal duction, particularly adduction, deforms the disc and peripapillary vasculature. This deformation, which is larger in younger than older subjects, may be due to optic nerve tethering in adduction.
| S-EPMC6911619 | biostudies-literature
Project description:PurposeGuinea pigs are increasingly being used as a model of myopia, and may also represent a novel model of glaucoma. Here, optical coherence tomography (OCT) imaging was performed in guinea pigs. In vivo measurements of retinal, choroidal, and optic nerve head parameters were compared with histology, and repeatability and interocular variations were assessed.MethodsOCT imaging and histology were performed on adult guinea pigs (n = 9). Using a custom program in MATLAB, total retina, ganglion cell/nerve fiber layer (GC/NFL), outer retina, and choroid thicknesses were determined. Additionally, Bruch's membrane opening (BMO) area and diameter, and minimum rim width were calculated. Intraobserver, interocular, and intersession coefficients of variation (CV) and intraclass correlation coefficients (ICC) were assessed.ResultsRetina, GC/NFL, outer retina and choroid thicknesses from in vivo OCT imaging were 147.7 ± 5.8 μm, 59.2 ± 4.5 μm, 72.4 ± 2.4 μm, and 64.8 ± 11.6 μm, respectively. Interocular CV ranged from 1.8% to 11% (paired t-test, p = 0.16 to 0.81), and intersession CV ranged from 1.1% to 5.6% (p = 0.12 to 0.82), with the choroid showing the greatest variability. BMO area was 0.192 ± 0.023 mm2, and diameter was 493.79 ± 31.89 μm, with intersession CV of 3.3% and 1.7%, respectively. Hyper reflective retinal layers in OCT correlated with plexiform and RPE layers in histology.ConclusionIn vivo OCT imaging and quantification of guinea pig retina and optic nerve head parameters were repeatable and similar between eyes of the same animal. In vivo visibility of retinal cell layers correlated well with histological images.Abbreviationsoptic nerve head (ONH), retinal ganglion cell (RGC), spectral domain optical coherence tomography (SD-OCT), enhanced depth imaging (EDI), minimum rim width (MRW), hematoxylin and eosin (H & E).
| S-EPMC6097717 | biostudies-literature