Identification of novel phosphodiesterase (PDE)-modulating compounds and characterization of associated cytoprotective pathways in lightdamagedretina

光损伤视网膜中新型磷酸二酯酶 (PDE) 调节化合物的鉴定和相关细胞保护途径的表征

• 批准号: 10552001
• 负责人: Jennings C Luu
• 金额: $ 5.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552001
• 关键词: Adverse effects; Affect; Age related macular degeneration; Aging; Apoptotic; Binding; Biology; Blindness; Caffeine; Cardiovascular Physiology; Cell Death; Cell Survival; Chronic; Clinical; Combined Modality Therapy; Computer Assisted; Consumption; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Cytoprotection; Data; Development; Disease; Dose; Drug Design; Drug Industry; Drug Targeting; Dryness; Engineering; Enzymes; Erectile dysfunction; Exclusion; Exhibits; Functional disorder; Goals; Human; Human body; Immune system; Intervention; Investments; Knockout Mice; Lead; Learning; Light; Link; Maintenance; Memory; Metabolism; Methods; Modeling; Molecular; Neurobiology; North America; PDE2 phosphodiesterase; Pathogenesis; Pathologic; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphodiesterase Inhibitors; Photoreceptors; Phototoxicity; Phototransduction; Physiological; Physiological Processes; Play; Prevalence; Preventive therapy; Process; Protein Isoforms; RNA Splicing; Recording of previous events; Reproduction; Retina; Retinal Degeneration; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Stress; System; Systems Biology; Therapeutic Agents; Therapeutic Effect; Tissues; Treatment Efficacy; Validation; Variant; Viagra; Vision; cell type; combat; drug action; effective therapy; immunoregulation; improved; in silico; in vivo; inhibitor; inhibitor therapy; innovation; insight; molecular dynamics; mouse model; novel; novel therapeutics; pharmacologic; phosphoric diester hydrolase; preservation; prevent; protective effect; repaired; response; screening; side effect; synergism; targeted agent

PROJECT SUMMARY Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes ubiquitously expressed in the human body, and they play a critical role in a broad range of physiological processes, including regulation of the immune system, cardiovascular function, metabolism, reproduction, neurobiological processes of learning and memory, and vision. PDEs function enzymatically to hydrolyze intracellular cyclic nucleotide second messengers (cAMP and cGMP), thereby affecting various downstream cellular signaling pathways that control homeostatic processes. These include repair mechanisms that promote cell survival (somatic maintenance), as well as pro- apoptotic mechanisms that result in cell death. In aging and disease, dysregulation of these signaling networks can lead to a reduced investment in somatic maintenance, resulting in pathophysiological states of disease. However, as key regulatory nodes that modulate intracellular and subcellular concentrations of second messenger signaling molecules, it is conceivable that PDEs could be pharmacologically targeted in order to upregulate pathways that improve cellular viability in disease states. By integrating recent advances in PDE biology with high-throughput methods, this proposal aims to identify new PDE-targeting agents and further characterize the pathways through which they alleviate pathophysiology in chronic, debilitating disease. Specifically, our focus will be on the application of newly identified therapeutic agents to ameliorating disease in a mouse model of retinal degeneration. Our long-term goal is to obtain a better understanding of the role played by PDE-dependent signaling pathways in the pathogenesis of retinal degeneration and to develop interventions that stop the progression of human blinding diseases. Accordingly, we propose three thematically and experimentally linked Specific Aims, to: 1) identify novel PDE- modulating compounds through in silico screening, 2) evaluate the therapeutic efficacy of PDE-selective inhibitors in preventing retinal degeneration, and 3) validate a systems pharmacology approach to optimizing PDE inhibitor therapy. Successful completion of Aim 1 will result in the discovery of novel compounds that circumvent the limitations of existing PDE inhibitors and exhibit superior targeting selectivity with enhanced potential for clinical utility. Through completion of Aim 2, we intend to demonstrate a statistically significant therapeutic effect conferred by PDE inhibition that is robustly conserved across different mouse models of retinal degeneration. Lastly, successful completion of Aim 3 will dissect the underlying molecular mechanisms of cytoprotection in the context of stress-induced retinal degeneration, thereby providing innovative systems biology insights on the synergism between intersecting networks involving crosstalk among the many different cell types in the retina. Indeed, these insights will facilitate a more unified perspective to attain our long-term goal of developing new and improved pharmaceutical interventions to combat human blindness.

项目总结