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：
7159394
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/7159394
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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：谷氨酸激活介导快速突触传递的离子型谷氨酸受体（iGluR）和调节细胞兴奋性的代谢型谷氨酸受体（mGluR）。 iGluR 控制细胞外钠和钙进入细胞，而 I 组 mGluR (1, 5) 导致细胞内储存的钙释放。中风或缺血等脑损伤会导致细胞外谷氨酸增加、iGluR 和 mGluR 不受控制的激活以及细胞内钙的毒性积累，而细胞内钙是细胞死亡的重要引发剂。因此，治疗脑缺血的治疗策略集中于使用iGluR和I组mGluR拮抗剂。虽然 iGluR 拮抗剂在模拟缺血研究中具有神经保护作用，可能是由于抑制细胞内钙积累，但这些化合物在临床试验中失败了。类似地，I 组 mGluR 拮抗剂在模型缺血研究中具有神经保护作用，可能是由于抑制细胞内钙积累，但将大多数 mGluR 选择性化合物递送至大脑是困难的。我们已经开始使用蛋白质组学来探索脑缺血的替代神经保护策略，以识别通过药理学可及的细胞外氨基末端结构域相互作用来调节 I 组 mGluR 信号传导的新型蛋白质或肽。我们的第一个蛋白质组学研究集中于 I 组 mGluR 亚型 mGluRS，并揭示了与最近克隆的促进细胞存活的细胞外蛋白 ADNP（活性依赖性神经保护蛋白）之间的新相互作用。 ADNP 含有八个氨基酸肽序列（NAPVSIPQ；NAP），它被证明是 ADNP 中可诱导神经保护的最小活性元件。临床前实验表明，NAP 具有有效的神经保护、增强记忆和神经营养特性。然而，NAP 或 ADNP 神经保护的机制尚不清楚。我们的初步数据表明，NAP 和 ADNP 的神经保护机制之一是调节 I 组 mGluR 信号传导。本文提出的研究很重要，因为 1) 它们开始描述 NAP（一种外源性肽）和 ADNP（一种内源性蛋白质）的神经保护机制，2) 它们为肽或蛋白质相互作用对 mGluR 信号传导的新调节提供了证据。细胞外域，3）它们为脑缺血的治疗干预提供了新方法。