Methamphetamine Induces a Complex Microglia-Neuronal Crosstalk

描述（由申请人提供）：甲基苯丙胺滥用在美国继续以惊人的速度增长。长期使用这种药物可导致严重的神经和精神损伤以及人类明显的神经退行性变化。本研究旨在明确甲基苯丙胺治疗后导致小胶质细胞活化和细胞损伤的分子级联反应。在这个高度集中的研究项目中，我们希望测试新的假设，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醌）从儿茶酚胺能细胞中解放出来，而儿茶酚胺能细胞反过来与小胶质细胞中的AMPA受体相互作用。我们进一步假设暴露于TOPA醌的小胶质细胞通过AMPA受体介导的过程被激活，并随后通过定义的分子级联诱导进一步的细胞损伤。这是一项由研究者发起的小额资助（R03）申请，要求有限的资金来测试一个明确的假设，并有明确的目标。这是一个小型的，独立的研究项目，符合美国国立卫生研究院公告PA-06-180中概述的R03支持描述。这些研究可以为使用治疗药物来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：本文提出的研究旨在定义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。这些研究可以为使用治疗药物来预防甲基苯丙胺暴露后的神经元损伤提供基础。

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.