Methamphetamine and Astrocyte Function

甲基苯丙胺和星形胶质细胞功能

• 批准号: 7220624
• 负责人: KHANH V TRAN
• 金额: $ 3.46万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-07 至 2008-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220624
• 关键词: AIDS neuropathy; Astrocytes; Attention; Biological Response Modifiers; Blood - brain barrier anatomy; Brain; Brain Pathology; Buffers; CCR5 gene; CXCR4 gene; Cell Proliferation; Cells; Cessation of life; Class; Condition; Data; Dementia; Development; Dissection; Drug usage; Encephalopathies; Family; Feline Immunodeficiency Virus; Fellowship; Glutamates; HIV-1; Homeostasis; Immune; Immune response; In Vitro; Incidence; Individual; Infection; Inflammation; Ion Channel; Iran; Knowledge; Laboratories; Ligands; Macrophage Inflammatory Proteins; Measures; Mediator of activation protein; Metabolic; Methamphetamine; Microglia; Modeling; Molecular; Morphology; Names; Neuroglia; Neurons; Neurotransmitter Receptor; Pathogenesis; Pathologic; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Plastics; Play; Positioning Attribute; Process; RANTES; Receptor Signaling; Recycling; Regulation; Role; Signal Pathway; Signaling Molecule; Source; Stromal Cells; Synaptic Transmission; System; Testing; Therapeutic Intervention; Toxic effect; Viral; chemokine; chemokine receptor; cytokine; drug of abuse; immune function; macrophage; member; migration; monocyte chemoattractant protein-2; neuroinflammation; neurotoxic; neurotoxicity; neurotrophic factor; psychostimulant; receptor; relating to nervous system; response; synergism

DESCRIPTION (provided by applicant): During the last decade, chemokines and their receptors have emerged as important signaling molecules in processes regulating neuronal migration, cell proliferation, synaptic transmission, neuronal inflammation and degeneration. Chemokine receptors, CXCR4 and CCR5, act as coreceptors for HIV-1, drawing attention to this intriguing class of immune mediators. Epidemiological data connecting HIV-1 associated dementia to drug of use, particularly methamphetamine (METH), suggest that stimulants may enhance HIV-1 neurotoxicity. Although the mechanism(s) of this neurotoxic synergism is not fully understood, METH may alter neural immune responses that could play a role in its pharmacology, including neurotoxicity, or contribute to the neuronal effects of other factors. Whether and how METH modulates immune function in brain is not known. Astrocytes express chemokines and their receptors and they may be key players in the regulation of chemokine system in CMS. Studies suggest astrocytes contribute to the pathogenesis of lentiviral encephalopathy and METH enhances viral infectivity of astrocytes via chemokine receptors. My hypothesis is that METH modulates chemokine function in astrocytes, and in doing so alters their ability to act as buffer system to maintain brain homeostasis impacting plastic and pathologic responses. Primary astrocytes are used as a model to investigate the effects of METH and other stimulants on chemokine responses and their role in astrocyte function. In this regard, the following Specific Aims will be investigated: Aim 1: To explore the effects of METH on chemokines, their receptors and signaling pathways. Aim 2: To determine the effects of METH on astrocyte proliferation and phenotype, and the role of chemokines.

描述（由申请人提供）：在过去的十年中，趋化因子及其受体在调节神经元迁移，细胞增殖，突触传播，神经元炎症和变性的过程中已成为重要的信号分子。趋化因子受体CXCR4和CCR5充当HIV-1的共感受器，引起人们对这种有趣类别的免疫介质的关注。将HIV-1相关痴呆与使用药物相关的流行病学数据，尤其是甲基苯丙胺（METH），这表明刺激剂可能会增强HIV-1神经毒性。尽管该神经毒性协同作用的机制尚未完全了解，但甲基苯丙胺可能会改变可能在其药理学（包括神经毒性）中发挥作用的神经免疫反应，或者有助于其他因素的神经元作用。 METH是否以及如何调节大脑中的免疫功能尚不清楚。星形胶质细胞表达趋化因子及其受体，它们可能是CMS趋化因子系统调节的关键参与者。研究表明，星形胶质细胞有助于慢病毒脑病的发病机理，而甲基苯甲酸甲酯通过趋化因子受体增强了星形胶质细胞的病毒感染性。我的假设是，MET在星形胶质细胞中调节了趋化因子功能，并在这样做会改变其作为缓冲系统维持脑稳态的能力，从而影响塑性和病理反应。主要的星形胶质细胞被用作研究甲基苯甲酸反应及其在星形胶质细胞功能中的作用的影响。在这方面，将研究以下特定目的：目标1：探索甲基苯丙胺对趋化因子，其受体和信号通路的影响。目标2：确定甲基对星形胶质细胞增殖和表型的影响以及趋化因子的作用。