Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition.

Autor: Luu JC; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Saadane A; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Leinonen H; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697.; Department of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland., Choi EH; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Gao F; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Lewandowski D; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Halabi M; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Sander CL; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Wu A; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Wang JM; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195., Singh R; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195., Gao S; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106., Lessieur EM; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Dong Z; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Palczewska G; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Mullins RF; Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA 52242., Peachey NS; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195.; Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106.; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195., Kiser PD; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697.; Department of Physiology & Biophysics, School of Medicine, University of California-Irvine, Irvine, CA 92697.; Research Service, VA Long Beach Healthcare System, Long Beach, CA 90822.; Department of Clinical Pharmacy Practice, University of California-Irvine, Irvine, CA 92697., Tabaka M; International Centre for Translational Eye Research, Warsaw 01224, Poland.; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01224, Poland., Kern TS; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697., Palczewski K; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California-Irvine, Irvine, CA 92697.; Department of Physiology & Biophysics, School of Medicine, University of California-Irvine, Irvine, CA 92697.; International Centre for Translational Eye Research, Warsaw 01224, Poland.; Department of Chemistry, University of California-Irvine, Irvine, CA 92697.; Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA 92697.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 09; Vol. 120 (19), pp. e2221045120. Date of Electronic Publication: 2023 May 01.
DOI: 10.1073/pnas.2221045120
Abstrakt: 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.
Databáze: MEDLINE