The effects of abnormal prion protein accumulation on retinal morphology and function in sheep and cattle

Transmissible spongiform encephalopathies (TSE) encompass a group of unique, invariably fatal neurodegenerative diseases, which affect humans and animals. Accumulation of an abnormal form of the prion protein (PrPSc) in the central nervous system serves as their pathologic underpinning. The pathogenesis of TSE remains unclear, and the specific effects of PrPSc on cells of the nervous system have yet to be completely resolved. Previous studies have identified the accumulation of PrP Sc within the retina, the thin, highly organized piece of neural tissue lining the posterior aspect of the eye. The purpose of this dissertation was to investigate the effects of PrPSc accumulation on retinal cellular morphology and function.;Using morphologic and functional analyses, we have identified alterations in retinal cellular morphology and function in sheep and cattle infected with TSE. We examined the effects of PrPSc on retinal cellular morphology in sheep affected with their naturally occurring TSE, scrapie, using immunohistochemistry (IHC). We demonstrated alteration of immunoreactivity patterns of rod bipolar cell, retinal ganglion cell, and Muller glia specific markers. Immunoreactivity patterns of cholinergic amacrine cell and conventional synapse markers were similar to scrapie free control sheep. In cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy (TME), we combined functional (electroretinography) and morphologic (IHC) analyses to investigate the impact of TSE infection on the bovine retina. We demonstrated altered retinal function during the preclinical phase of disease, evidenced by prolonged ERG b-wave implicit time, and during the clinical phase, evidenced by prolonged implicit time and decreased amplitude of the b-wave. Morphologic abnormalities consistent with spongiform change were demonstrated in the retina of TME-affected cattle, and immunoreactivity patterns of rod bipolar cell and Muller glia markers were altered. Our results contribute novel and important information on the response of the retina to TSE

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 128, May 1974

This special bibliography lists 282 reports, articles, and other documents introduced into the NASA scientific and technical information system in April 1974

Optic Nerve Head Remodeling In Experimental High Myopia

Myopia is a global health concern, with projected estimates that nearly half of the world\u27s population will be myopic by 2050. While its refractive aspect can be corrected, the heightened susceptibility to sight-threatening comorbidities, particularly with high myopia, remains a challenge. Among these comorbidities, glaucoma is a major concern, with myopia recognized as an independent risk factor. However, the mechanistic link between myopia and glaucoma remains poorly understood. This dissertation investigates the multiscale remodeling changes in experimental high myopia and their potential implications for increased risk of glaucoma later in life. Using a multimodal approach, this dissertation investigates: (1) neural canal opening remodeling and thickness changes of peripapillary tissues during juvenile high myopia development, (2) the impact of sustained high myopia on peripapillary tissues from juvenile age until early adulthood, and (3) changes in retinal function, optic nerve axonal counts, and retinal proteomics during juvenile high myopia development. The findings of these studies revealed that juvenile experimental high myopia induces progressive asymmetric deformations of the neural canal opening and heterogeneous thinning of peripapillary tissues, where the retina was relatively protected. Furthermore, sustained negative lens wear into early adulthood induced progressive myopia in a subset of eyes, where profound choroidal thinning during early myopia development emerged as a potential biomarker for future chorioscleral thinning and myopia progression. Lastly, while retinal function and optic nerve axonal counts were preserved during the juvenile stage of myopia, retinal proteomics identified differential modulation of key molecular pathways that may serve to protect the retina against various myopia-induced insults. These findings advance our understanding of the myopia remodeling changes and may suggest mechanistic links between myopia and glaucoma. The observed asymmetric remodeling of the neural canal opening and peripapillary tissues may alter the biomechanical environment at the ONH, potentially increasing the risk of pathological ONH remodeling and subsequent glaucoma development later in life. Moreover, the identified retinal protective mechanisms may become exhausted with aging, thereby heightening susceptibility to neurodegenerative conditions such as glaucoma. Lastly, this work identifies a potential biomarker for predicting progressive myopia, thereby offering novel avenues for early intervention and targeted therapeutic strategies

Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies

The Retina in Health and Disease

Vision is the most important sense in higher mammals. The retina is the first step in visual processing and the window to the brain. It is not surprising that problems arising in the retina lead to moderate to severe visual impairments. We offer here a collection of reviews as well as original papers dealing with various aspects of retinal function as well as dysfunction. New approaches in retinal research are described, such as the expression and localization of the endocannabinoid system in the normal retina and the role of cannabinoid receptors that could offer new avenues of research in the development of potential treatments for retinal diseases. Moreover, new insights are offered in advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP, and diabetic retinopathy

Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies

Glaucoma

This book addresses the basic and clinical science of glaucomas, a group of diseases that affect the optic nerve and visual fields and is usually accompanied by increased intraocular pressure. The book incorporates the latest development as well as future perspectives in glaucoma, since it has expedited publication. It is aimed for specialists in glaucoma, researchers, general ophthalmologists and trainees to increase knowledge and encourage further progress in understanding and managing these complicated diseases

Modulation of the intraocular immune environment by viral gene transfer in mouse models of uveitis

Treatment options for severe uveitis are predominantly limited to systemic immunosuppressants, which are often accompanied by significant side effects. Ocular gene transfer, though, may serve as a sustained local immunomodulating therapy. New adeno-associated virus (AAV) serotypes were used to investigate gene therapy for uveitis in mouse models. Experimental autoimmune uveoretinitis (EAU) was used to model human disease; whilst endotoxin induced uveitis (EIU) was employed to dissect factors affecting immune suppression by AAV. Refinement of AAV production processes improved the quality of vectors including AAV8, AAV9 and ShH10. Technical issues were assessed, confirming apical transgene secretion from RPE and examining the effects of endotoxin contamination. New methods for the evaluation and quantitative scoring of disease severity in both animal models were developed, based on flow cytometry and optical coherence tomography (OCT) for EIU and EAU in C57BL/6J mice, respectively. The complexity of the role of IL-10 in EAU became evident, and pronounced species differences between murine and human IL-10 were identified in EIU. Despite generating intraocular levels comparable to those of recombinant protein known to be effective, AAV-derived human IL-10 did not suppress EIU. Gene delivery of soluble monomeric TNF receptors did not suppress EAU or EIU, and in vitro exhibited less TNF neutralising effects than an equivalent dimeric Fc-fusion protein. Local expression of this dimeric protein from different vectors however was also unable to attenuate EAU. An NFκB-motif based promoter to regulate the expression of AAV-delivered transgenes in uveitis was developed in parallel. It demonstrated activation only in the presence of, and in proportion to the degree of inflammation in EAU. Despite these advances, neither IL-10 nor TNF-inhibitors proved optimal targets for local suppression of intraocular inflammation by AAV. Further work is needed to assess the response of the eye to viral gene transfer in the context of uveitis

Aerospace Medicine and Biology: A continuing bibliography with indexes (supplement 250)

This bibliography lists 265 reports, articles and other documents introduced into the NASA scientific and technical information system in September 1983