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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）：