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Methamphetamine Induces a Complex Microglia-Neuronal Crosstalk

甲基苯丙胺诱导复杂的小胶质细胞神经元串扰

基本信息

批准号：
7847033
负责人：
Elias Aizenman
金额：
$ 0.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847033
关键词：
AMPA Receptors Accounting Agonist Attenuated Brain Catecholamines Cells Chronic Complex Dependence Drug usage Event Funding Glutamate Receptor Grant Human Impairment Lead Link MAP Kinase Gene MAPK14 gene Mediating Methamphetamine Microglia Modeling Molecular N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurologic Neuronal Injury Neurons Nitrogen Oxidative Stress Oxidopamine Oxygen Pathway interactions Peroxonitrite Process Property Quinones Rattus Reactive Oxygen Species Request for Applications Research Research Personnel Research Project Grants Signal Transduction Testing Therapeutic Agents Toxic effect United States National Institutes of Health base cell injury cytotoxic dopaminergic neuron drug of abuse high risk methamphetamine abuse methamphetamine exposure monoamine neurotoxic neurotoxicity novel oxidation prevent public health relevance public health research stimulant abuse

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine abuse continues to increase in the US at alarming rates. Chronic use of this drug can lead to severe neurological and psychiatric impairments as well as to pronounced neurodegenerative changes in humans. The research proposed here is intended to define the molecular cascade leading to microglia activation and subsequent cellular injury following methamphetamine treatment. In this highly focused research project we wish to test the novel hypothesis that methamphetamine exposure leads to the liberation of the monoamine-derived glutamate receptor agonist 2, 4, 5-trihydroxyphenylalanine quinone (TOPA quinone) from catecholaminergic cells, which, in turn interacts with AMPA receptors in microglia. We further hypothesize microglia exposed to TOPA quinone become activated via an AMPA receptor-mediated process and can subsequently induce further cellular damage via a defined molecular cascade. This is an Investigator-Initiated Small Grant (R03) application requesting limited funds to test a defined hypothesis with focused objectives. This is a small, self-contained research project fitting a description for R03 support outlined in NIH announcement PA-06-180. These studies could provide a basis by which therapeutic agents may be used to prevent neuronal injury following methamphetamine exposure. PUBLIC HEALTH RELEVANCE: The research proposed here is intended to define the molecular cascade leading to microglia activation and subsequent neuronal injury following methamphetamine treatment. These studies could provide a basis by which therapeutic agents may be used to prevent neuronal injury following methamphetamine exposure.

描述(申请人提供)：甲基苯丙胺滥用在美国继续以惊人的速度增加。长期使用这种药物会导致严重的神经和精神损害，以及人类明显的神经退行性变化。这项研究旨在确定甲基苯丙胺治疗后导致小胶质细胞激活和随后的细胞损伤的分子级联反应。在这个高度集中的研究项目中，我们希望检验这一新的假设，即甲基苯丙胺暴露导致单胺衍生的谷氨酸受体激动剂2，4，5-三羟基苯丙氨酸醌(Topa Quone)从儿茶酚胺能细胞中释放出来，进而与小胶质细胞中的AMPA受体相互作用。我们进一步假设，暴露于Topa Quinone的小胶质细胞通过AMPA受体介导的过程被激活，随后可以通过定义的分子级联反应诱导进一步的细胞损伤。这是一个由调查人员发起的小额赠款(R03)申请，请求有限的资金来测试具有重点目标的已定义假说。这是一个小型的、独立的研究项目，符合NIH公告PA-06-180中概述的R03支持的描述。这些研究可能为治疗剂用于预防甲基苯丙胺暴露后的神经元损伤提供基础。公共卫生相关性：这里提出的研究旨在确定甲基苯丙胺治疗后导致小胶质细胞激活和随后的神经元损伤的分子级联反应。这些研究可能为治疗剂用于预防甲基苯丙胺暴露后的神经元损伤提供基础。