Tag Archives: retinal remodeling

Metabolic changes and retinal remodeling in Heterozygous CRX mutant cats (CRXRDY/+)

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We have a new manuscript from the lab in Experimental Eye Research, (PubMed link here). Metabolic changes and retinal remodeling in Heterozygous CRX mutant cats (CRXRDY/+). This manuscript is in collaboration with the Simon Petersen-Jones lab out of Michigan State University.  Authors are: Laurence M. Occelli, Bryan W. Jones @BWJones, Taylor J. Cervantes, and Simon M. Petersen-Jones. The PDF is here.

Abstract: CRX is a transcription factor essential for normal photoreceptor development and survival. The CRXRdy cat has a naturally occurring truncating mutation in CRX and is a large animal model for dominant Leber congenital amaurosis. This study investigated retinal remodeling that occurs as photoreceptors degenerate. CRXRdy/+ cats from 6 weeks to 10 years of age were investigated. In vivo structural changes of retinas were analyzed by fundus examination, confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. Histologic analyses including immunohistochemistry for computational molecular phenotyping with macromolecules and small molecules. Affected cats had a cone-led photoreceptor degeneration starting in the area centralis. Initially there was preservation of inner retinal cells such as bipolar, amacrine and horizontal cells but with time migration of the deafferented neurons occurred. Early in the process of degeneration glial activation occurs ultimately resulting in formation of a glial seal. With progression the macula-equivalent area centralis developed severe atrophy including loss of retinal pigmentary epithelium. Microneuroma formation occurs in advanced stages as more marked retinal remodeling occurred. This study indicates that retinal degeneration in the CrxRdy/+ cat retina follows the progressive, phased revision of retina that have been previously described for retinal remodeling. These findings suggest that therapy dependent on targeting inner retinal cells may be useful in young adults with preserved inner retinas prior to advanced stages of retinal remodeling and neuronal cell loss.

Current Perspective on Retinal Remodeling: Implications for Therapeutics

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We have a new paper out of the lab, a perspectives paper on Retinal Remodeling: Implications for Therapeutics. (pdf here).

Authors are Rebecca L. Pfeiffer @BeccaPfeiffer19, and Bryan W. Jones @BWJones.

Abstract: The retinal degenerative diseases retinitis pigmentosa and age-related macular degeneration are a leading cause of irreversible vision loss. Both present with progressive photoreceptor degeneration that is further complicated by processes of retinal remodeling. In this perspective, we discuss the current state of the field of retinal remodeling and its implications for vision-restoring therapeutics currently in development. Here, we discuss the challenges and pitfalls retinal remodeling poses for each therapeutic strategy under the premise that understanding the features of retinal remodeling in totality will provide a basic framework with which therapeutics can interface. Additionally, we discuss the potential for approaching therapeutics using a combined strategy of using diffusible molecules in tandem with other vision-restoring therapeutics. We end by discussing the potential of the retina and retinal remodeling as a model system for more broadly understanding the progression of neurodegeneration across the central nervous system.

Model-Based Comparison of Current Flow in Rod Bipolar Cells of Healthy and Early-Stage Degenerated Retina

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We have a new manuscript out in Experimental Eye Research, Model-Based Comparison of Current Flow in Rod Bipolar Cells of Healthy and Early-Stage Degenerated Retina. (pdf here)

Authors: Pragya Kosta, Ege Iseri, Kyle Loizos, Javad Paknahad, Rebecca L. Pfeiffer @BeccaPfeiffer19, Crystal L. Sigulinsky @CLSigulinsky, James R. Anderson, Bryan W. Jones @BWJones, and Gianluca Lazzi.

Abstract: Retinal degenerative diseases, such as retinitis pigmentosa, are generally thought to initiate with the loss of photoreceptors, though recent work suggests that plasticity and remodeling occurs prior to photoreceptor cell loss. This degeneration subsequently leads to death of other retinal neurons, creating functional alterations and extensive remodeling of retinal networks. Retinal prosthetic devices stimulate the surviving retinal cells by applying external current using implanted electrodes. Although these devices restore partial vision, the quality of restored vision is limited. Further knowledge about the precise changes in degenerated retina as the disease progresses is essential to understand how current flows in retinas undergoing degenerative disease and to improve the performance of retinal prostheses. We developed computational models that describe current flow from rod photoreceptors to rod bipolar cells

 

Model-based Comparison of Current Flow in Rod Bipolar Cells of Healthy and Early-Stage Degenerated Retina

Editorial: Special Issue on Retinal Remodeling

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Geoff Lewis and I worked over the last year or so to edit a special issue of Experimental Eye Research with a focus on Retinal Remodeling.  Our editorial for the issue is here. Pubmed link is here.

This special issue of Experimental Eye Research represents laboratories around the world that are involved in retinal degeneration research and was developed with two motivations: 1) to solicit manuscripts from our colleagues that would give broad, yet substantial insight into the various disorders associated with retinal degeneration and 2) to focus discussion in the vision research community into the negative plasticity now known as retinal remodeling that is associated with blinding diseases…

We selected an image for the cover from the Calkins lab (the center image in the above montage) that we felt was beautiful and represented the quality of work that went into every article in this issue and look forward to the dialogue that this special issue will foster.  Many thanks to: The Lewis/Fisher lab, the Calkins lab, the Vetter lab, the Lutty lab, the Gross lab, the Sagdullaev lab, the Merriman lab and Wei Li, Michael Kalloniatis and the Fletcher lab, the Cuenca lab, the Acosta lab, and everyone in our lab.

Retinal Remodeling And Metabolic Alterations in Human AMD

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We have a new publication out (direct link, open access), Müller Cell Metabolic Chaos During Retinal Degeneration authored by Bryan W. Jones, Rebecca Pfeiffer, William Ferrell, Carl Watt, James Tucker, and Robert Marc.

Abstract:

Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.

Retinal Remodeling in Human Retinitis Pigmentosa

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We have a new publication out (Direct Link, Free Open Access), Retinal Remodeling in Human Retinitis Pigmentosa authored by Bryan W. Jones, Rebecca Pfeiffer, Drew Ferrell, Carl Watt, Michael Marmor and Robert Marc.

Abstract: Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

Webvision Chapter: Retinal Degeneration, Remodeling and Plasticity

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We have published a new chapter in Webvision, Retinal Degeneration, Remodeling and Plasticity that covers the history of the study of retinal degenerations and some of the implications for vision rescue.  Authors are Bryan W. Jones, Rebecca L. Pfeiffer and Robert E. Marc.  It will, like other Webvision chapters evolve over time, which is the whole point of Webvision, but we hope it will generate some discussion.