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
基本信息
- 批准号:10418610
- 负责人:
- 金额:$ 5.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adverse effectsAffectAge related macular degenerationAgingApoptoticBindingBiologyBlindnessCaffeineCardiovascular PhysiologyCell DeathCell SurvivalChronicClinicalCombined Modality TherapyComputer AssistedConsumptionCyclic AMPCyclic GMPCyclic NucleotidesCytoprotectionDataDevelopmentDiseaseDoseDrug DesignDrug IndustryDrug TargetingEngineeringEnzymesErectile dysfunctionExhibitsFunctional disorderGoalsHumanHuman bodyImmune systemInterventionInvestmentsKnockout MiceLeadLearningLightLinkMaintenanceMemoryMetabolismMethodsModelingMolecularNeurobiologyNorth AmericaPDE2 phosphodiesterasePathogenesisPathologicPathway interactionsPersonsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhosphodiesterase InhibitorsPhotoreceptorsPhototoxicityPhototransductionPhysiologicalPhysiological ProcessesPlayPrevalencePreventive therapyProcessProtein IsoformsRNA SplicingRecording of previous eventsReproductionRetinaRetinal DegenerationRoleSecond Messenger SystemsSignal PathwaySignal TransductionSignaling MoleculeSpecificityStressSystemSystems BiologyTherapeutic AgentsTherapeutic EffectTissuesTreatment EfficacyValidationVariantViagraVisioncell typecombateffective therapyimmunoregulationimprovedin silicoin vivoinhibitorinhibitor therapyinnovationinsightmolecular dynamicsmouse modelnovelnovel therapeuticsphosphoric diester hydrolasepreservationpreventprotective effectrepairedresponsescreeningside effectsynergismtargeted agent
项目摘要
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.
项目概要
环核苷酸磷酸二酯酶(PDE)是一类在人体内普遍表达的酶,
它们在广泛的生理过程中发挥着关键作用,包括免疫调节
系统,心血管功能,新陈代谢,生殖,学习和记忆的神经生物学过程,
和愿景。 PDE 通过酶促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细胞信号传导途径
流程。这些包括促进细胞存活(体细胞维持)的修复机制,以及亲
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
可能导致躯体维护投入减少,从而导致疾病的病理生理状态。
然而,作为调节细胞内和亚细胞浓度的关键调节节点
作为信使信号分子,可以想象 PDE 可以在药理学上被靶向,以便
上调改善疾病状态下细胞活力的途径。通过整合 PDE 的最新进展
生物学与高通量方法,该提案旨在确定新的 PDE 靶向剂并进一步
描述了它们缓解慢性衰弱性疾病病理生理学的途径。
具体来说,我们的重点将是应用新发现的治疗药物来改善疾病
视网膜变性的小鼠模型。我们的长期目标是更好地了解所扮演的角色
研究视网膜变性发病机制中 PDE 依赖性信号通路的作用并制定干预措施
阻止人类致盲疾病的进展。
因此,我们提出了三个主题和实验相关的具体目标,以:1)识别新的 PDE-
通过计算机筛选调节化合物,2) 评估 PDE 选择性的治疗效果
预防视网膜变性的抑制剂,以及 3) 验证优化系统药理学方法
PDE抑制剂治疗。目标 1 的成功完成将导致新化合物的发现,
规避现有 PDE 抑制剂的局限性,并通过增强的增强表现出优异的靶向选择性
临床应用的潜力。通过完成目标 2,我们打算证明具有统计显着性
PDE 抑制所带来的治疗效果在不同的视网膜小鼠模型中稳健保守
退化。最后,成功完成目标 3 将剖析潜在的分子机制
在应激引起的视网膜变性的情况下进行细胞保护,从而提供创新的系统生物学
关于涉及许多不同细胞类型之间串扰的交叉网络之间的协同作用的见解
在视网膜中。事实上,这些见解将有助于形成更统一的视角,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对抗人类失明。
项目成果
期刊论文数量(0)
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Jennings C Luu其他文献
Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
增强应激能力的药物通过抑制磷酸二酯酶来保护退化视网膜的组织结构和功能
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:11.1
- 作者:
Jennings C Luu;A. Saadane;Henri Leinonen;Elliot H Choi;Fangyuan Gao;Dominik Lewandowski;Maximilian Halabi;Christopher L Sander;Arum Wu;Jacob M Wang;Rupesh Singh;Songqi Gao;E. Lessieur;Zhiqian Dong;G. Palczewska;R. Mullins;N. Peachey;P. Kiser;M. Tabaka;T. Kern;Krzysztof Palczewski - 通讯作者:
Krzysztof Palczewski
Jennings C Luu的其他文献
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{{ truncateString('Jennings C Luu', 18)}}的其他基金
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:
10153237 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别:
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