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Small-Molecule Ligands of Rhodopsin and Their Therapeutic Potential in Retina Degeneration.

Rhodopsin, the prototypical Class A G protein-coupled receptor (GPCR) and visual pigment of rod photoreceptors, has long served as a structu … vancing rhodopsin-targeted therapeutics toward clinically credible interventions for RP and related retinal degenerations.

Dicer is essential for proper maturation, composition, and function in the postnatal retina.

The impact of Dicer/miRNAs during postnatal retinogenesis is unknown. This study aimed to deplete Dicer in postnatal retinal progenitor/precursor cells (RPCs/PCs) and to evaluate the structure and function of the adult Dicer-cKO retina using optical coherence tomography (OCT), electroretinography (ERG), and histology. We found impaired rod function, a significantly reduced number of rod bipolar cells and their associated functions, a decreased Müller glia population, and an increased population of HuC/D + Pax6/+ amacrine cells in the adult Dicer-cKO retina. Transcriptional analyses conducted i…

High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE/choroid explants in vitro. The resulting g…

Elevated PRDM13 Disrupts Photoreceptor Function and Survival in the Mammalian Retina.

PURPOSE: Retinal degeneration is a common cause of blindness, but there is a gap in our understanding of the molecular mechanisms causing degeneration. Dysregulated PRDM13 has been linked to retinal dystrophy, indicating a role for PRDM13 in the retina. PRDM13 knockout studies have shown that PRDM13 specifies amacrine cell fates, but no studies have shown the phenotypic and mechanistic outcomes of its elevated activity in the retina. METHODS: We developed a mouse model to induce aberrant PRDM13 expression in a controlled, time-dependent manner. ERG and histological analyses were performed to …

Melatonin Alleviates Retina Angiogenesis by Targeting Fibronectin and the VEGF Pathway.

Diabetic retinopathy (DR) and retinopathy of prematurity (ROP) continue to be significant causes of vision impairment despite the well-established role of vascular endothelial growth factor (VEGF) in pathological angiogenesis. We still need to deeply understand retinal angiogenesis's molecular mechanisms and identify potential alternate therapeutic targets. We used RNA sequencing (RNA-seq) and found fibronectin (FN1), an extracellular matrix protein, was significantly upregulated during retinal angiogenesis in the oxygen-induced retinopathy (OIR) model. Employing a deep learning model (BioNet)…

Steroid-Nitroxide Hybrid Compound Protects the Retina in a Model of CNV.

Nitroxide-based drugs have proven effective in modulating radical-induced oxidative stress by modulating antioxidant enzymes and genes that control distinct immune and anti-inflammatory responses. Due to their reasonable chemical stability and ability to shuttle between oxidized and reduced forms at physiologically relevant redox potentials, nitroxide-based radicals have also proven effective as biological probes of redox status. Herein, we investigated the potential of a unique nitroxide-based antioxidant and anti-inflammatory agent to protect the retina from experimentally induced degenerati…

Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies.

BACKGROUND: Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the cre

The P2X7 Receptor Regulates IL-1β Secretion in the Human Retina.

The P2X7 receptor has been associated with the neurodegeneration of retinal ganglion cells (RGCs), which is central to the loss of vision in glaucoma. Furthermore, the activation of P2X7 has been shown to cause the death of RGCs, including in the human retina. Human organotypic retinal cultures (HORCs) were used to investigate the potential indirect mechanisms of RGC death. Of the 27 cytokine/growth factors assayed, the stimulation of P2X7 using BzATP (100 µM; 36 h) significantly increased the secretion of IL-1β and IL-10. IL-1β was selected for further investigation. BzATP (100 µM) caused an …

Impact of a single session of hyperbaric oxygen therapy on the healthy retina.

BACKGROUND: Hyperoxia induced by hyperbaric oxygen therapy (HBOT) may lead to retinal vasoconstriction and the generation of reactive oxygen species. This study aims to investigate the effects of a single session of HBOT on the healthy retina using full-field electroretinography (ffERG) and spectral-domain optical coherence tomography (SD-OCT). METHODS: Twenty patients diagnosed with either sensorineural hearing loss or avascular necrosis, all of whom had an indication for HBOT, were included in the study. A comprehensive ophthalmologic examination, along with ffERG and SD-OCT assessments of …

The roles of glycerophospholipids in the aging retina and age-related macular degeneration.

Glycerophospholipids (GPs) are integral constituents of cellular membranes, and play a crucial role in the regulation of lipid metabolism homeostasis and physiological conditions. However, pathological alterations associated with aging, such as variations in plasma GP concentrations, disruptions in intercellular GP transport, and local accumulation of excessive GPs, have been observed. These changes induce irreversible cellular degeneration, ultimately leading to tissue damage in organs such as the brain and retina. A growing body of evidences has demonstrated that GPs play significant roles i…

Глубокое обучение и сетчатка: новая граница в многоклерозном диагностике.

Множественный склероз (MS) — хроническое аутоиммунное заболевание центральной нервной системы, которое приводит к нейродегенерации и функциональным расстройствам. Поскольку последние достижения в области сетчатки сетчатки показали, что сетчатка является неинвазивным окном в мозг, предлагающим ценные биомаркеры для диагностирования и отслеживания прогресса MS, мы изучили интеграцию искусственного интеллекта (AI), особенно глубокого обучения (DL), в анализ таких основанных на фондах методов снимков, как оптическая гармония (OCT), фотография фонда и сканирующая лазерная офтальмоскопия (SLO). Эти

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that leads to neurodegeneration and functional disability. Because recent advances in retinal imaging have revealed that the retina is a non-invasive window into the brain, offering valuable biomarkers for MS diagnosis and progression tracking, we explored the integration o…

A possible origin of the inverted vertebrate retina revealed by physical modeling.

The evolutionary origin of the inverted retina in the vertebrate eye is unknown. This paper explores a hypothetical evolutionary scenario that explains the unique orientation of the photoreceptors in the vertebrate retina. The proposed scenario follows the scientific accepted scenario for eye evolution and gradually builds up towards an eye prototype by considering light direction detection and increase in achievable spatial resolution as the driving forces. It suggests that eye retinas developed along two different morphological processes, an evagination process that results in the inverted r…

Optical coherence tomography angiography of the retina and choroid in systemic diseases.

Optical coherence tomography angiography (OCTA) has transformed ocular vascular imaging, revealing microvascular changes linked to various systemic diseases. This review explores its applications in diabetes, hypertension, cardiovascular diseases, and neurodegenerative diseases. While OCTA provides a valuable window into the body's microvasculature, interpreting the findings can be complex. Additionally, challenges exist due to the relative non-specificity of its findings where changes observed in OCTA might not be unique to a specific disease, variations between OCTA machines, the lack of a s

Physics-informed deep generative learning for quantitative assessment of the retina.

Disruption of retinal vasculature is linked to various diseases, including diabetic retinopathy and macular degeneration, leading to vision loss. We present here a novel algorithmic approach that generates highly realistic digital models of human retinal blood vessels, based on established biophysical principles, including fully-connected arterial and venous trees with a single inlet and outlet. This approach, using physics-informed generative adversarial networks (PI-GAN), enables the segmentation and reconstruction of blood vessel networks with no human input and which out-performs human lab…

Lack of FMRP in the retina: Evidence of a retinal specific transcriptomic profile.

Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability, is a monogenic neurodevelopmental disorder caused … d been described in the FXS patients as well as in the murine model (Fmr1-/ymice), characterized by retinal deficits associated to retinal perception alterations. However, although the transcriptomic profile in the absence of FMRP has been studied in the cerebral part of the central nervous system (CNS), there are no actual data for the retina which is a …

The gut-retina axis: Uncovering the role of autoimmunity in glaucoma development.

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve damage. While elevated intraocular pressure (IOP) is the only known modifiable risk factor, normal-tension glaucoma (NTG) challenges this notion, suggesting other mechanisms beyond IOP may contribute to its development. Emerging evidence support the hypothesis that glaucoma may be an autoimmune disease. This review summarizes evidence for this hypothesis, focusing on the gut-retina axis. We discuss how antigens of gut bacterial prime peripheral T …

Cholecystokinin receptor type A are involved in the circadian rhythm of the mouse retina.

The retina is the only organ projecting external light to the suprachiasmatic nucleus. Cholecystokinin receptor type A (Cckar/Cckar) is one of the essential factors for light reception in retinal cells. As there was a lack of literature on the matter, we aimed to elucidate the cause of the time-dependent phase change in clock gene expression. We found that Cckar mRNA expression in retinal cells exhibited diurnal variations. The rhythm of expression of the clock gene Per1/Per2 in retinal cells was altered in Cckar -/- mice. The light sensitivity of retinal cells was evaluated in wild-type mice,…

Neurovascular changes of the retina and optic nerve head in episodic migraine.

To investigate neurovascular changes; including macular vascular density (VD), thickness of the ganglion cell layer (GCL) and optic nerve he … was significantly reduced in the central ring (GCL + p = 0.042, GCL +  + p = 0.029), as well as the retinal nerve fiber layer (RNFL) thickness in the temporal quadrant (p = 0.021) and border tissue of Elschnig diameter (BTE, p = 0.035). The duration of migraine showed an inverse correlation with SCP in the nasal quadrant (p = 0.016, r = - 0.445) and with …

Deletion of Transmembrane protein 184b leads to retina degeneration in mice.

Transmembrane protein 184b (Tmem184b) has been implicated in axon degeneration and neuromuscular junction dysfunction. Notably, Tmem184b exhibits high expression levels in the retina; however, its specific function within this tissue remains poorly understood. To elucidate the role of Tmem184b in the mammalian visual system, we developed a Tmem184b knockout (KO) model for further investigation. Loss of Tmem184b led to significant decreases in both a and b wave amplitudes of scotopic electroretinogram (ERG) and reduced b wave amplitudes of photopic ERG, respectively, reflecting damage to both t…

The receptive field construction of midget ganglion cells in primate retina.

The midget pathway of the primate retina provides the visual system with the foundations for high spatial resolution and color perception. An essential contributor to these properties is center-surround organization, in which responses from the central area of a cell's receptive field are antagonized by responses from a surrounding area. Two key questions about center-surround organization are unresolved. First, the surround is largely or completely due to negative feedback from horizontal cells to cones: how can this feedback be reconciled with the popular difference of Gaussians (DOG) model,…