Pan-Lipoxygenase Inhibitors for CNS Disease
治疗中枢神经系统疾病的泛脂氧合酶抑制剂
基本信息
- 批准号:8084158
- 负责人:
- 金额:$ 37.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAmyloid beta-ProteinAnimal ModelAnimalsAntioxidantsApoptosisArachidonate 12-LipoxygenaseArachidonate 15-LipoxygenaseArachidonate 5-LipoxygenaseAsthmaBehaviorBehavioralBiological AssayBrainCategoriesCell Culture TechniquesCell DeathCell SurvivalCellsCentral Nervous System DiseasesChronicClinicDiseaseElectron TransportEnzymesExcisionFoundationsGene DeletionGenesGlucoseGlutamatesGlutathioneGoalsHumanHuntington DiseaseIn VitroInflammationIschemiaIschemic StrokeKnock-outKnockout MiceLeadLipoxygenaseLipoxygenase InhibitorsLiteratureMass Spectrum AnalysisMediatingMemory impairmentMetabolicMetabolic Clearance RateMetabolismMitochondriaModelingMolecularMolecular BiologyMolecular TargetMusNerve Cell SurvivalNervous System TraumaNervous system structureNeurodegenerative DisordersNeuronsOryctolagus cuniculusOxidative StressParkinson DiseasePathologyPathway interactionsPharmaceutical PreparationsPhospholipasePhosphoproteinsPhosphorylationPlayPreclinical Drug EvaluationProceduresProductionProstaglandin-Endoperoxide SynthaseProteinsProteomicsReactive Oxygen SpeciesReportingRoleSclerosisScreening procedureSeriesSignal PathwaySiteSolidStarvationStrokeSubstrate SpecificitySystemTechnologyTestingToxic effectToxinTransgenic AnimalsTransgenic MiceTransgenic OrganismsWithdrawalWorkage relatedbasedefined contributiondesigndrug candidatedrug developmenteffective therapyexcitotoxicityextracellularfatty acid metabolisminsightlipid metabolismmild neurocognitive impairmentnew therapeutic targetpreventprotein aggregatepublic health relevanceresearch studysmall moleculetherapeutic targettool
项目摘要
DESCRIPTION (provided by applicant): There are currently no effective cures or treatments for chronic CNS conditions such as Alzheimer's disease (AD) and stroke. We and others have shown that the activation of lipoxygenases (LOXs) play a central role in the nerve cell death associated with both disorders because LOX inhibitors reduce nerve cell death in both cell culture studies and in animal models that mimic these disorders. Furthermore, LOXs are highly elevated in AD and mild cognitive impairment, and AD transgenic animals in which the various LOXs and the phospholipases that provide LOX substrates are genetically deleted have greatly reduced pathology. However, the molecular mechanisms by which LOX enzymes are activated and how their products cause nerve cell death are unknown. Nor have CNS therapies based upon LOX metabolism been extensively tested in animal models. To understand the signaling pathways and gain better insight into potential therapeutic targets, we will study LOX-mediated nerve cell death in two robust cell culture models of chronic oxidative stress and intracellular beta amyloid toxicity. Both paradigms are associated with the depletion of glutathione and ROS production. In addition, LOX inhibitors enhance the removal of aggregated protein, a condition associated with AD and aging in general. Using these experimental systems, we will answer the following questions. What is the mechanism by which the depletion of glutathione activates LOXs and how do the LOX metabolites stimulate ROS production from mitochondria? What are the specific LOX products involved in both ROS production and the cell death pathways? What are the molecular signaling pathways involved? How does the inhibition of LOX enzymatic activity increase the rate of clearance of aggregated intracellular amyloid and promote cell survival? Finally, we will determine if our best pan-LOX inhibitor is able to clear intracellular A¿, reduce AD pathology and behavioral deficits in a transgenic mouse AD model and define the contribution of the major LOX genes to AD pathology. These experiments will build a solid foundation for the role of LOX metabolism in nerve cell death and the metabolism of intracellular amyloid, test this pathway in animals, and identify new therapeutic targets.
PUBLIC HEALTH RELEVANCE: There are no cures or effective treatments for Alzheimer's disease or stroke, nor is it understood how and why nerve cells die in these conditions. On the basis of a very rigorous screening procedure we have identified a series of drug-like small molecules that are effective in animal models of Alzheimer's and stroke, but we do not understand the molecular pathways by which they are neuroprotective. To push these drugs to the clinic and to identify more and perhaps better therapeutic targets, we need to understand exactly how these drugs function, and that is the goal of this proposal.
描述(申请人提供):目前尚无治疗阿尔茨海默病(AD)和中风等慢性中枢神经系统疾病的有效方法。我们和其他人已经证明,脂氧合酶(LOX)的激活在与这两种疾病相关的神经细胞死亡中发挥着核心作用,因为LOX抑制剂在细胞培养研究和模拟这些疾病的动物模型中都减少了神经细胞的死亡。此外,LOX在AD和轻度认知障碍中高度升高,在AD转基因动物中,各种LOX和提供LOX底物的磷脂酶基因缺失,大大降低了病理程度。然而,LOX酶被激活的分子机制及其产物如何导致神经细胞死亡尚不清楚。基于LOX代谢的中枢神经系统疗法也没有在动物模型中得到广泛测试。为了了解信号通路并更好地了解潜在的治疗靶点,我们将在两种稳定的慢性氧化应激和细胞内淀粉样蛋白毒性的细胞培养模型中研究LOX介导的神经细胞死亡。这两种模式都与谷胱甘肽和ROS产生的耗竭有关。此外,LOX抑制剂可增强聚集蛋白的清除,这是一种与AD和衰老相关的情况。使用这些实验系统,我们将回答以下问题。谷胱甘肽耗竭激活LOXs的机制是什么?LOX代谢物如何刺激线粒体产生ROS?在ROS产生和细胞死亡途径中都涉及哪些特定的LOX产物?有哪些分子信号通路参与其中?LOX酶活性的抑制如何增加聚集在细胞内的淀粉样蛋白的清除速度并促进细胞存活?最后,我们将确定我们最好的PAN-LOX抑制剂是否能够清除细胞内A?,减少转基因小鼠AD模型中的AD病理和行为缺陷,并确定主要LOX基因在AD病理中的作用。这些实验将为LOX代谢在神经细胞死亡和细胞内淀粉样蛋白代谢中的作用奠定坚实的基础,在动物身上测试这一途径,并确定新的治疗靶点。
与公共卫生相关:目前还没有治疗阿尔茨海默病或中风的有效方法,也不清楚神经细胞在这些情况下是如何死亡的以及为什么死亡。在非常严格的筛选程序的基础上,我们已经确定了一系列类似药物的小分子,这些小分子在阿尔茨海默氏症和中风的动物模型中有效,但我们不知道它们具有神经保护作用的分子途径。为了将这些药物推向临床,并确定更多甚至更好的治疗靶点,我们需要确切地了解这些药物是如何发挥作用的,这就是这项提议的目标。
项目成果
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DAVID R SCHUBERT其他文献
DAVID R SCHUBERT的其他文献
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{{ truncateString('DAVID R SCHUBERT', 18)}}的其他基金
Characterization of a Potent Neurogenic Compound
强效神经源性化合物的表征
- 批准号:
8374346 - 财政年份:2012
- 资助金额:
$ 37.54万 - 项目类别:
Characterization of a Potent Neurogenic Compound
强效神经源性化合物的表征
- 批准号:
8461542 - 财政年份:2012
- 资助金额:
$ 37.54万 - 项目类别:
Pan-Lipoxygenase Inhibitors for CNS Disease
治疗中枢神经系统疾病的泛脂氧合酶抑制剂
- 批准号:
8680099 - 财政年份:2010
- 资助金额:
$ 37.54万 - 项目类别:
Pan-Lipoxygenase Inhibitors for CNS Disease
治疗中枢神经系统疾病的泛脂氧合酶抑制剂
- 批准号:
8490268 - 财政年份:2010
- 资助金额:
$ 37.54万 - 项目类别:
Pan-Lipoxygenase Inhibitors for CNS Disease
治疗中枢神经系统疾病的泛脂氧合酶抑制剂
- 批准号:
8290360 - 财政年份:2010
- 资助金额:
$ 37.54万 - 项目类别:
Pan-Lipoxygenase Inhibitors for CNS Disease
治疗中枢神经系统疾病的泛脂氧合酶抑制剂
- 批准号:
7986374 - 财政年份:2010
- 资助金额:
$ 37.54万 - 项目类别:
A Novel Family of Neuroprotective Compounds for Stroke
治疗中风的新型神经保护化合物家族
- 批准号:
7928155 - 财政年份:2009
- 资助金额:
$ 37.54万 - 项目类别:
A Novel Family of Neuroprotective Compounds for Stroke
治疗中风的新型神经保护化合物家族
- 批准号:
7655854 - 财政年份:2009
- 资助金额:
$ 37.54万 - 项目类别:
Development and Testing of a Novel Neuroprotective Drug
新型神经保护药物的开发和测试
- 批准号:
7140561 - 财政年份:2005
- 资助金额:
$ 37.54万 - 项目类别: