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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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