权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuroprotection by Novel Regulators of mGluR Signaling

mGluR 信号传导的新型调节剂的神经保护作用

基本信息

批准号：
7341708
负责人：
JULIE Anne SAUGSTAD
金额：
$ 30.48万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-16 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341708
关键词：
Address Adenylate Cyclase Affect Agonist Amino Acid Neurotransmitters Amino Acids Apoptosis Astrocytes Behavioral Binding Biological Assay Brain Brain Injuries Brain Ischemia Calcium Caspase Cell Death Cell Survival Cells Chemosensitization Chimeric Proteins Clinical Trials Culture Media Data Deletion Mutagenesis Dose Elements Excitatory Amino Acids Excitatory Postsynaptic Potentials Extracellular Domain Extracellular Protein Ganciclovir Glucose Glutamate Receptor Glutamates Glutathione S-Transferase Hippocampus (Brain)Hour Hydrolysis Image In Vitro Infarction Ischemia Knockout Mice Lead Mass Spectrum Analysis Measures Mediating Memory Metabotropic Glutamate Receptors Middle Cerebral Artery Occlusion Modeling N-Methyl-D-Aspartate Receptors Neuraxis Neuroglia Neurons Outcome Oxygen Peptide Signal Sequences Peptides Phosphatidylinositols Physiological Property Proteins Proteomics RNA Interference Rattus Regulation Research Personnel Role Signal Transduction Small RNA Sodium Specificity Staining method Stains Stroke Synaptic Transmission System Testing Therapeutic Therapeutic Intervention deprivation dihydroxyphenylethylene glycol extracellular injured metabotropic glutamate receptor type 1 molecular site neuroprotection novel novel strategies pre-clinical preconditioning programs protein aminoacid sequence protein expression research study response

项目摘要

Glutamate activates ionotropic glutamate receptors (iGluRs) that mediate fast synaptic transmission, and metabotropic glutamate receptors (mGluRs) that modulate cell excitability. The iGluRs gate extracellular sodium and calcium entry into the cell, while the Group I mGluRs (1, 5) lead to the release of calcium from intracellular stores. Brain injury such as stroke or ischemia leads to increased extracellular glutamate, uncontrolled activation of iGluRs and mGluRs, and the toxic accumulation of intracellular calcium that is an essential initiator of cell death. Thus therapeutic strategies for the treatment of brain ischemia have focused on the use of iGluR and Group I mGluR antagonists. While iGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, these compounds have failed in clinical trials. Similarly, Group I mGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, yet delivery of most mGluR-selective compounds to the brain is difficult. We have begun to explore alternative neuroprotective strategies for brain ischemia using proteomics to identify novel proteins or peptides that modulate Group I mGluR signaling via interactions at the pharmacologically accessible extracellular amino terminal domain. Our first proteomic studies focused on the Group I mGluR subtype, mGluRS, and revealed a novel interaction with a recently cloned extracellular protein that promotes cell survival, ADNP (activity-dependent neuroprotective protein). ADNP contains an eight amino acid peptide sequence (NAPVSIPQ; NAP) that was shown to be the smallest active element of ADNP that can induce neuroprotection. Preclinical experiments show that NAP has potent neuroprotective, memory enhancing and neurotrophic properties. However, the mechanisms that underlie neuroprotection by NAP or ADNP are not known. Our preliminary data suggest that one mechanism of neuroprotection by NAP and ADNP is to regulate Group I mGluR signaling. The research studies proposed herein are important because 1) they begin to delineate the mechanisms of neuroprotection by NAP, an exogenous peptide, and ADNP, an endogenous protein, 2) they provide evidence for the novel regulation of mGluR signaling by peptide or protein interactions at the extracellular domain, and 3) they offer new approaches for therapeutic intervention in brain ischemia.

谷氨酸激活离子性谷氨酸受体（iGluRs），介导快速突触传递