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Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, lead...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175720/ https://www.ncbi.nlm.nih.gov/pubmed/37126699 http://dx.doi.org/10.1073/pnas.2221045120 |
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author | C. Luu, Jennings Saadane, Aicha Leinonen, Henri H. Choi, Elliot Gao, Fangyuan Lewandowski, Dominik Halabi, Maximilian L. Sander, Christopher Wu, Arum Wang, Jacob M. Singh, Rupesh Gao, Songqi Lessieur, Emma M. Dong, Zhiqian Palczewska, Grazyna Mullins, Robert F. Peachey, Neal S. Kiser, Philip D. Tabaka, Marcin Kern, Timothy S. Palczewski, Krzysztof |
author_facet | C. Luu, Jennings Saadane, Aicha Leinonen, Henri H. Choi, Elliot Gao, Fangyuan Lewandowski, Dominik Halabi, Maximilian L. Sander, Christopher Wu, Arum Wang, Jacob M. Singh, Rupesh Gao, Songqi Lessieur, Emma M. Dong, Zhiqian Palczewska, Grazyna Mullins, Robert F. Peachey, Neal S. Kiser, Philip D. Tabaka, Marcin Kern, Timothy S. Palczewski, Krzysztof |
author_sort | C. Luu, Jennings |
collection | PubMed |
description | Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness. |
format | Online Article Text |
id | pubmed-10175720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-101757202023-11-01 Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition C. Luu, Jennings Saadane, Aicha Leinonen, Henri H. Choi, Elliot Gao, Fangyuan Lewandowski, Dominik Halabi, Maximilian L. Sander, Christopher Wu, Arum Wang, Jacob M. Singh, Rupesh Gao, Songqi Lessieur, Emma M. Dong, Zhiqian Palczewska, Grazyna Mullins, Robert F. Peachey, Neal S. Kiser, Philip D. Tabaka, Marcin Kern, Timothy S. Palczewski, Krzysztof Proc Natl Acad Sci U S A Biological Sciences Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness. National Academy of Sciences 2023-05-01 2023-05-09 /pmc/articles/PMC10175720/ /pubmed/37126699 http://dx.doi.org/10.1073/pnas.2221045120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences C. Luu, Jennings Saadane, Aicha Leinonen, Henri H. Choi, Elliot Gao, Fangyuan Lewandowski, Dominik Halabi, Maximilian L. Sander, Christopher Wu, Arum Wang, Jacob M. Singh, Rupesh Gao, Songqi Lessieur, Emma M. Dong, Zhiqian Palczewska, Grazyna Mullins, Robert F. Peachey, Neal S. Kiser, Philip D. Tabaka, Marcin Kern, Timothy S. Palczewski, Krzysztof Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title | Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title_full | Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title_fullStr | Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title_full_unstemmed | Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title_short | Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
title_sort | stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175720/ https://www.ncbi.nlm.nih.gov/pubmed/37126699 http://dx.doi.org/10.1073/pnas.2221045120 |
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