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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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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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2221045120</identifier><identifier>PMID: 37126699</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-05, Vol.120 (19), p.e2221045120</ispartof><rights>Copyright National Academy of Sciences May 9, 2023</rights><rights>Copyright © 2023 the Author(s). Published by PNAS. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-41bb84834bdf6a2b59775dbed2bb84834cddd3ec31ed1dfea02523d7fa2768743</citedby><cites>FETCH-LOGICAL-c422t-41bb84834bdf6a2b59775dbed2bb84834cddd3ec31ed1dfea02523d7fa2768743</cites><orcidid>0000-0002-8748-4532 ; 0000-0001-8762-5473 ; 0000-0001-9120-0291 ; 0000-0002-0788-545X ; 0000-0002-0388-832X ; 0000-0001-7283-0335 ; 0000-0003-1184-9539 ; 0000-0002-4419-7226 ; 0000-0002-2233-5501</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175720/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175720/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37126699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luu, Jennings C</creatorcontrib><creatorcontrib>Saadane, Aicha</creatorcontrib><creatorcontrib>Leinonen, Henri</creatorcontrib><creatorcontrib>Choi, Elliot H</creatorcontrib><creatorcontrib>Gao, Fangyuan</creatorcontrib><creatorcontrib>Lewandowski, Dominik</creatorcontrib><creatorcontrib>Halabi, Maximilian</creatorcontrib><creatorcontrib>Sander, Christopher L</creatorcontrib><creatorcontrib>Wu, Arum</creatorcontrib><creatorcontrib>Wang, Jacob M</creatorcontrib><creatorcontrib>Singh, Rupesh</creatorcontrib><creatorcontrib>Gao, Songqi</creatorcontrib><creatorcontrib>Lessieur, Emma M</creatorcontrib><creatorcontrib>Dong, Zhiqian</creatorcontrib><creatorcontrib>Palczewska, Grazyna</creatorcontrib><creatorcontrib>Mullins, Robert F</creatorcontrib><creatorcontrib>Peachey, Neal S</creatorcontrib><creatorcontrib>Kiser, Philip D</creatorcontrib><creatorcontrib>Tabaka, Marcin</creatorcontrib><creatorcontrib>Kern, Timothy S</creatorcontrib><creatorcontrib>Palczewski, Krzysztof</creatorcontrib><title>Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><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.</description><subject>3',5'-Cyclic-nucleotide phosphodiesterase</subject><subject>Age</subject><subject>Age related diseases</subject><subject>Bioaccumulation</subject><subject>Biological Sciences</subject><subject>Blindness</subject><subject>Diabetes mellitus</subject><subject>Diabetic Retinopathy - metabolism</subject><subject>Eye diseases</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Intracellular signalling</subject><subject>Macular degeneration</subject><subject>Macular Degeneration - pathology</subject><subject>Molecular modelling</subject><subject>Nucleotides</subject><subject>Pathogenesis</subject><subject>Perturbation</subject><subject>Pharmacology</subject><subject>Proteomes</subject><subject>Proteomics</subject><subject>Resilience</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retinal degeneration</subject><subject>Retinal Degeneration - metabolism</subject><subject>Retinitis</subject><subject>Retinitis pigmentosa</subject><subject>Retinitis Pigmentosa - metabolism</subject><subject>Retinopathy</subject><subject>Structure-function relationships</subject><subject>Transcriptomes</subject><subject>Transcriptomics</subject><subject>Visual perception</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtv1DAUhS0EokNhzQ5ZYsMm7fUjsbNCqIKCVIkFsLYc-2bGVcYJdjwSO346nnYoj4V9JZ_vHvnoEPKSwQUDJS6XaPMF55yBbBmHR2TDoGdNJ3t4TDYAXDVacnlGnuV8CwB9q-EpOROK8a7r-w35-WVNmDOtV5gCRocNxp2NLsQt9alsM12qhumAdA05F6R5TcWtJSG10dOxRLeGOdIQqcctRkx2PS4nrMPSQ7B02c25Hh8wr1XOWOFdGMJx7zl5Mtop44vTPCffPrz_evWxufl8_enq3U3jJOdrI9kwaKmFHPzYWT60vVKtH9Dz07vz3gt0gqFnfkQLvOXCq9Fy1WklxTl5e--7lGGP3mFck53MksLeph9mtsH8q8SwM9v5YBgw1SoO1eHNySHN30uNYvYhO5wmG3Eu2XANutWtYLyir_9Db-eSYs1XKSZAargzvLynXJpzTjg-_IaBOdZrjvWaP_XWjVd_h3jgf_cpfgH0KqYa</recordid><startdate>20230509</startdate><enddate>20230509</enddate><creator>Luu, Jennings C</creator><creator>Saadane, Aicha</creator><creator>Leinonen, Henri</creator><creator>Choi, Elliot H</creator><creator>Gao, Fangyuan</creator><creator>Lewandowski, Dominik</creator><creator>Halabi, Maximilian</creator><creator>Sander, Christopher L</creator><creator>Wu, Arum</creator><creator>Wang, Jacob M</creator><creator>Singh, Rupesh</creator><creator>Gao, Songqi</creator><creator>Lessieur, Emma M</creator><creator>Dong, Zhiqian</creator><creator>Palczewska, Grazyna</creator><creator>Mullins, Robert F</creator><creator>Peachey, Neal S</creator><creator>Kiser, Philip D</creator><creator>Tabaka, Marcin</creator><creator>Kern, Timothy S</creator><creator>Palczewski, Krzysztof</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8748-4532</orcidid><orcidid>https://orcid.org/0000-0001-8762-5473</orcidid><orcidid>https://orcid.org/0000-0001-9120-0291</orcidid><orcidid>https://orcid.org/0000-0002-0788-545X</orcidid><orcidid>https://orcid.org/0000-0002-0388-832X</orcidid><orcidid>https://orcid.org/0000-0001-7283-0335</orcidid><orcidid>https://orcid.org/0000-0003-1184-9539</orcidid><orcidid>https://orcid.org/0000-0002-4419-7226</orcidid><orcidid>https://orcid.org/0000-0002-2233-5501</orcidid></search><sort><creationdate>20230509</creationdate><title>Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-41bb84834bdf6a2b59775dbed2bb84834cddd3ec31ed1dfea02523d7fa2768743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>3',5'-Cyclic-nucleotide phosphodiesterase</topic><topic>Age</topic><topic>Age related diseases</topic><topic>Bioaccumulation</topic><topic>Biological Sciences</topic><topic>Blindness</topic><topic>Diabetes mellitus</topic><topic>Diabetic Retinopathy - metabolism</topic><topic>Eye diseases</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Intracellular signalling</topic><topic>Macular degeneration</topic><topic>Macular Degeneration - pathology</topic><topic>Molecular modelling</topic><topic>Nucleotides</topic><topic>Pathogenesis</topic><topic>Perturbation</topic><topic>Pharmacology</topic><topic>Proteomes</topic><topic>Proteomics</topic><topic>Resilience</topic><topic>Retina</topic><topic>Retina - metabolism</topic><topic>Retinal degeneration</topic><topic>Retinal Degeneration - metabolism</topic><topic>Retinitis</topic><topic>Retinitis pigmentosa</topic><topic>Retinitis Pigmentosa - metabolism</topic><topic>Retinopathy</topic><topic>Structure-function relationships</topic><topic>Transcriptomes</topic><topic>Transcriptomics</topic><topic>Visual perception</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Luu, Jennings C</creatorcontrib><creatorcontrib>Saadane, Aicha</creatorcontrib><creatorcontrib>Leinonen, Henri</creatorcontrib><creatorcontrib>Choi, Elliot H</creatorcontrib><creatorcontrib>Gao, Fangyuan</creatorcontrib><creatorcontrib>Lewandowski, Dominik</creatorcontrib><creatorcontrib>Halabi, Maximilian</creatorcontrib><creatorcontrib>Sander, Christopher L</creatorcontrib><creatorcontrib>Wu, Arum</creatorcontrib><creatorcontrib>Wang, Jacob M</creatorcontrib><creatorcontrib>Singh, Rupesh</creatorcontrib><creatorcontrib>Gao, Songqi</creatorcontrib><creatorcontrib>Lessieur, Emma M</creatorcontrib><creatorcontrib>Dong, Zhiqian</creatorcontrib><creatorcontrib>Palczewska, Grazyna</creatorcontrib><creatorcontrib>Mullins, Robert F</creatorcontrib><creatorcontrib>Peachey, Neal S</creatorcontrib><creatorcontrib>Kiser, Philip D</creatorcontrib><creatorcontrib>Tabaka, Marcin</creatorcontrib><creatorcontrib>Kern, Timothy S</creatorcontrib><creatorcontrib>Palczewski, Krzysztof</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luu, Jennings C</au><au>Saadane, Aicha</au><au>Leinonen, Henri</au><au>Choi, Elliot H</au><au>Gao, Fangyuan</au><au>Lewandowski, Dominik</au><au>Halabi, Maximilian</au><au>Sander, Christopher L</au><au>Wu, Arum</au><au>Wang, Jacob M</au><au>Singh, Rupesh</au><au>Gao, Songqi</au><au>Lessieur, Emma M</au><au>Dong, Zhiqian</au><au>Palczewska, Grazyna</au><au>Mullins, Robert F</au><au>Peachey, Neal S</au><au>Kiser, Philip D</au><au>Tabaka, Marcin</au><au>Kern, Timothy S</au><au>Palczewski, Krzysztof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2023-05-09</date><risdate>2023</risdate><volume>120</volume><issue>19</issue><spage>e2221045120</spage><pages>e2221045120-</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>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. 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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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