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：
8429444
负责人：
David Thoms Stark
金额：
$ 0.37万
依托单位：
LSU HEALTH SCIENCES CENTER
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：
https://reporter.nih.gov/project-details/8429444
关键词：
ALOX15 gene Action Potentials Affect Agonist Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Arachidonate 15-Lipoxygenase Attenuated Bathing Biochemistry Biological Availability Biomedical Research Brain Brain-Derived Neurotrophic Factor Calcium Cell Culture Techniques Cell Death Cell Survival Cells Cellular biology Cessation of life Cyclic AMP-Responsive DNA-Binding Protein Dependence Development Disease Docosahexaenoic Acids Enzymes Epilepsy Equilibrium Exhibits Fluo-3 Functional disorder Gene Expression Genes Health Healthcare High Pressure Liquid Chromatography Hippocampus (Brain)Human Image In Vitro Injury Ischemia Link Lipids Lipoxygenase 1 Measures Mediating Mediator of activation protein Mitochondria Modeling Molecular Molecular Biology Mus N-Methyl-D-Aspartate Receptors Necrosis Neurodegenerative Disorders Neurons Outcome Pathology Pathway interactions Patients Physiological Process Protocols documentation Receptor Signaling Regulation Reperfusion Therapy Research Retinal Role Signal Transduction Societies Stroke Synapses Techniques Testing Touch sensation Toxic effect Wild Type Mouse base brain cell care burden excitotoxicity improved in vivo lipid mediator mitochondrial dysfunction neuronal survival neuroprotectin D1 neuroprotection novel programs research study response tandem 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.

描述（由申请人提供）：这项拟议的研究是长期努力的一部分，旨在了解脂质信号传导机制如何决定受表现出兴奋性毒性细胞死亡的疾病影响的脑细胞的命运。刺激突触 NMDA 受体可促进神经元存活，而刺激突触外 NMDA 受体会导致显性的促死亡信号传导。然而，决定这两种结果的分子途径尚未完全了解。来自这些空间上不同的 NMDA 受体亚群的信号传导分别诱导两个基本上不重叠的基因表达程序，分别介导细胞存活和细胞死亡。神经保护 D1 (NPD1) 是一种源自二十二碳六烯酸 (DMA) 的立体特异性脂质介质，可激活人脑和视网膜细胞中的促生存基因表达程序。 NPD1 是否介导突触 NMDA 受体的促生存信号？将使用原代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。实验将重点关注脑源性神经营养因子 (BDNF) 对 NPD1 池大小的调节，BDNF 是突触 NMDA 受体促生存信号传导的介质，也是已知的 NPD1 合成激动剂。实验将采用细胞和分子生物学和生物化学技术、基于 HPLC-ESI 串联质谱的脂质组学分析，以及使用无法合成 NPD1 的 15-脂氧合酶-1 (15-LOX-1) 缺陷小鼠。拟议研究的结果将证明，来自突触 NMDA 受体的促生存信号是通过增加 BDNF 表达来增强 NPD1 池大小来介导的。此外，15-LOX-1 缺陷神经元培养物将比野生型培养物更容易受到兴奋性毒性损伤，并且 NPD1 将在体外和体内减弱兴奋性毒性损伤。