Regulation of Neuroprotective Lipid Sgnals by Spatially Distinct NMDA Receptors
空间上不同的 NMDA 受体对神经保护性脂质信号的调节
基本信息
- 批准号:7675075
- 负责人:
- 金额:$ 2.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:ALOX15 geneAction PotentialsAffectAgonistAlzheimer&aposs DiseaseAnti-Inflammatory AgentsAnti-inflammatoryApoptosisApoptoticArachidonate 15-LipoxygenaseAttenuatedBathingBiochemistryBiological AvailabilityBiomedical ResearchBrainBrain-Derived Neurotrophic FactorCalciumCell Culture TechniquesCell DeathCell SurvivalCellsCellular biologyCessation of lifeCyclic AMP-Responsive DNA-Binding ProteinDependenceDevelopmentDiseaseDocosahexaenoic AcidsEnzymesEpilepsyEquilibriumExhibitsFluo-3Functional disorderGene ExpressionGenesHealthcareHigh Pressure Liquid ChromatographyHippocampus (Brain)HumanImageIn VitroInjuryIschemiaLifeLinkLipidsLipoxygenase 1MeasuresMediatingMediator of activation proteinMitochondriaModelingMolecularMolecular BiologyMolecular and Cellular BiologyMusN-Methyl-D-Aspartate ReceptorsNecrosisNeurodegenerative DisordersNeuronsOutcomeOverlapping GenesPathologyPathway interactionsPatientsPhysiologicalProcessProtocols documentationReceptor SignalingRegulationReperfusion TherapyResearchRetinalRoleSignal TransductionSocietiesStrokeSynapsesTechniquesTestingTouch sensationToxic effectWild Type Mousebasebrain cellcare burdenexcitotoxicityimprovedin vivolipid mediatormitochondrial dysfunctionneuronal survivalneuroprotectin D1neuroprotectionnovelprogramspublic health relevanceresearch studyresponsetandem mass spectrometry
项目摘要
DESCRIPTION (provided by applicant):
The proposed research is part of a long-term effort to understand how lipid signaling mechanisms determine the fate of brain cells affected by diseases which exhibit excitotoxic cell death. Stimulation of synaptic NMDA receptors promotes neuronal survival, while stimulation of extrasynaptic NMDA receptors leads to dominant, pro-death signaling. However, the molecular pathways that determine these two outcomes are not fully understood. Two largely non-overlapping gene expression programs mediating cell survival and cell death, respectively, are induced by signaling from these spatially distinct NMDA receptor subpopulations. Neuroprotection D1 (NPD1) is a stereospecific lipid mediator derived from docosahexaenoic acid (DMA) that activates a pro-survival gene expression program in human brain and retinal cells. Does NPD1 mediate pro- survival signals from synaptic NMDA receptors? Control of NPD1 bioavailability by synaptic and extrasynaptic NMDA receptors will be investigated using primary hippocampal cell cultures. Experiments will focus on NPD1 pool size regulation by brain-derived neurotrophic factor (BDNF), which is a mediator of pro- survival signaling from synaptic NMDA receptors and a known agonist of NPD1 synthesis. Experiments will employ techniques from cell and molecular biology and biochemistry, HPLC-ESI tandem mass spectrometry-based lipidomic analysis, and the use of 15-lipoxygenase-1 (15-LOX-1) deficient mice, which are incapable of NPD1 synthesis. The results of the proposed studies will demonstrate that pro-survival signaling from the synaptic NMDA receptor is mediated through enhancement of the NPD1 pool size via increased expression of BDNF. Additionally, 15-LOX-1 deficient neuronal cultures will be shown to be significantly more vulnerable to excitotoxic injury than wild type cultures, and NPD1 will be shown to attenuate excitotoxic injury in vitro and in vivo. PUBLIC HEALTH RELEVANCE: Stroke, epilepsy, and neurodegenerative diseases such as Alzheimer's Disease, which share calcium toxicity as a common pathological feature, represent tremendous health care burdens on society and touch countless lives globally. Understanding the balance of molecular level processes leading to cell death or survival is critical to improving patient outcomes in these diseases, and neuroprotective signaling of DMA-derived lipid messengers is a new and important horizon on the biomedical research landscape.
描述(由申请人提供):
拟议的研究是长期努力的一部分,以了解脂质信号传导机制如何确定受兴奋性细胞死亡影响的脑细胞的命运。突触NMDA受体的刺激会促进神经元的存活,而刺激外突触NMDA受体会导致占主导地位,pro的死亡信号。但是,确定这两个结果的分子途径尚未完全了解。通过这些空间上不同的NMDA受体亚群的信号传导,分别介导细胞存活和细胞死亡的两个主要非重叠基因表达程序分别介导了细胞存活和细胞死亡。神经保护D1(NPD1)是源自二十六六烯酸(DMA)的立体型脂质介质,它激活了人脑和视网膜细胞中的促生存性基因表达程序。 NPD1是否介导了突触NMDA受体的促生存信号?将使用原发性海马细胞培养物研究突触和突触外NMDA受体对NPD1生物利用度的控制。实验将集中在脑衍生的神经营养因子(BDNF)的NPD1池大小调节上,该因子是突触NMDA受体的促生存信号传导的介体和NPD1合成的已知激动剂。实验将采用细胞和分子生物学和生物化学,基于HPLC-ESI串联质谱分析的技术,以及使用15-脂氧合酶-1(15-LOX-1)缺陷小鼠的使用,这些小鼠无能力由NPD1合成。拟议研究的结果将表明,来自突触NMDA受体的促生存信号传导是通过增加BDNF表达来增强NPD1池大小来介导的。此外,与野生型培养物相比,将证明15-LOX-1缺乏神经元培养物明显更容易受到兴奋性毒性损伤,并且NPD1将被证明可以减弱体外和体内的兴奋性毒性损伤。公共卫生相关性:中风,癫痫和神经退行性疾病,例如阿尔茨海默氏病,它们具有钙毒性作为一种共同的病理特征,代表了社会上的巨大医疗保健负担,并且在全球范围内触摸无数的生活。了解导致细胞死亡或存活的分子水平过程的平衡对于改善这些疾病的患者结局至关重要,而DMA衍生的脂质使者的神经保护信号传导是生物医学研究景观的新的重要视野。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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David Thoms Stark其他文献
David Thoms Stark的其他文献
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{{ truncateString('David Thoms Stark', 18)}}的其他基金
Regulation of Neuroprotective Lipid Sgnals by Spatially Distinct NMDA Receptors
空间上不同的 NMDA 受体对神经保护性脂质信号的调节
- 批准号:
8429444 - 财政年份:2009
- 资助金额:
$ 2.88万 - 项目类别:
Regulation of Neuroprotective Lipid Sgnals by Spatially Distinct NMDA Receptors
空间上不同的 NMDA 受体对神经保护性脂质信号的调节
- 批准号:
8231538 - 财政年份:2009
- 资助金额:
$ 2.88万 - 项目类别:
Regulation of Neuroprotective Lipid Sgnals by Spatially Distinct NMDA Receptors
空间上不同的 NMDA 受体对神经保护性脂质信号的调节
- 批准号:
8016002 - 财政年份:2009
- 资助金额:
$ 2.88万 - 项目类别:
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