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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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2023-05, Vol.120 (19), p.e2221045120
Hauptverfasser: Luu, Jennings C, Saadane, Aicha, Leinonen, Henri, Choi, Elliot H, Gao, Fangyuan, Lewandowski, Dominik, Halabi, Maximilian, Sander, Christopher L, 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
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container_issue 19
container_start_page e2221045120
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 120
creator Luu, Jennings C
Saadane, Aicha
Leinonen, Henri
Choi, Elliot H
Gao, Fangyuan
Lewandowski, Dominik
Halabi, Maximilian
Sander, Christopher L
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
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.
doi_str_mv 10.1073/pnas.2221045120
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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. 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subjects 3',5'-Cyclic-nucleotide phosphodiesterase
Age
Age related diseases
Bioaccumulation
Biological Sciences
Blindness
Diabetes mellitus
Diabetic Retinopathy - metabolism
Eye diseases
Homeostasis
Humans
Intracellular signalling
Macular degeneration
Macular Degeneration - pathology
Molecular modelling
Nucleotides
Pathogenesis
Perturbation
Pharmacology
Proteomes
Proteomics
Resilience
Retina
Retina - metabolism
Retinal degeneration
Retinal Degeneration - metabolism
Retinitis
Retinitis pigmentosa
Retinitis Pigmentosa - metabolism
Retinopathy
Structure-function relationships
Transcriptomes
Transcriptomics
Visual perception
title Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
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