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.

项目摘要 环核苷酸磷酸二酯酶（PDES）是一类在人体中表达的酶， 它们在广泛的生理过程中起着至关重要的作用，包括对免疫的调节 系统，心血管功能，代谢，繁殖，学习和记忆的神经生物学过程， 和愿景。 PDE在酶上发挥作用可水解细胞内环核苷酸第二信使（CAMP） 和CGMP），从而影响控制体内平衡的各种下游蜂窝信号传导途径 过程。这些包括促进细胞存活（体细胞维持）的修复机制，以及 导致细胞死亡的凋亡机制。在衰老和疾病中，这些信号网络的失调 可能导致对躯体维持的投资减少，从而导致疾病的病理生理状态。 但是，作为调节第二个细胞内和亚细胞浓度的关键调节节点 Messenger信号传导分子，可以想象可以将PDE用于药理目标，以便 上调改善疾病状态细胞活力的途径。通过整合PDE的最新进展 该建议旨在识别靶向PDE的剂，并进一步确定生物学的生物学。 表征它们减轻慢性衰弱疾病中病理生理学的途径。 具体而言，我们的重点将放在新近确定的治疗剂来改善疾病中的应用 视网膜变性的小鼠模型。我们的长期目标是更好地了解所发挥的作用 通过依赖PDE的信号通路，在视网膜变性的发病机理中并发展干预措施 这阻止了人类盲目疾病的进展。 因此，我们在主题和实验上提出了三个特定目标，以：1）确定新型的PDE- 调节化合物通过计算机筛选，2）评估PDE选择性的治疗功效 预防视网膜变性的抑制剂，3）验证系统药理学方法以优化 PDE抑制剂疗法。成功完成AIM 1将导致发现新颖的化合物 规避现有PDE抑制剂的局限性，并具有提高的靶向选择性 临床实用性的潜力。通过完成AIM 2，我们打算证明具有统计学意义 PDE抑制赋予的治疗效果在视网膜的不同小鼠模型中稳健保守 退化。最后，成功完成AIM 3将剖析基本的分子机制 在压力引起的视网膜变性的背景下，细胞保护作用，从而提供创新的系统生物学 关于涉及串扰的许多不同细胞类型之间的相交网络之间的协同作用的见解 在视网膜中。确实，这些见解将促进更统一的观点，以实现我们的长期目标 开发新的和改进的药物干预措施来打击人类失明。