Neuroimmune Cell Networks in Opioid Dependence and Withdrawal

阿片类药物依赖和戒断中的神经免疫细胞网络

基本信息

批准号：
8600490
负责人：
JAMES SCHWABER
金额：
$ 19.38万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600490
关键词：
Acute Affective Amygdaloid structure Anxiety Astrocytes Behavior Bioinformatics Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain region Cell Communication Cell Lineage Cell Nucleus Cell physiology Cells Chronic Collection Computational Biology Data Data Set Dependence Dependency Development Drug Addiction Drug abuse Emotional Emotions Endothelial Cells Epithelial Experimental Designs Gene Expression Gene Proteins Genes Genetic Transcription Genomics Immune response Immunologics Individual Inflammatory Inflammatory Response Intake Investigation Laboratories Lead Link Messenger RNA Microdissection Microfluidics Microglia Modeling Molecular National Institute of Drug Abuse Neuraxis Neuroglia Neuroimmunomodulation Neurons Neurophysiology - biologic function Opiate Addiction Opiates Opioid Opioid Receptor Outcome Pathology Population Process Processed Genes Protein Array Analysis Proteins Proteomics Publications Publishing Rattus Regulation Regulator Genes Research Research Personnel Role Sampling Symptoms System Testing Time Tissues Vascular Endothelial Cell Withdrawal Withdrawal Symptom Work addiction base brain tissue cell type chemokine cognitive function craving cytokine endogenous opioids experimental analysis high reward high risk improved in vivo innovation laser capture microdissection monocyte novel opioid withdrawal overdose death protein expression protein profiling public health relevance relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): Chronic opioid use changes the brain's state, including neuroimmune activity, impacting brain function and behavior and contributing to continued drug dependence and pathology. However, there is little work examining the progression of the cytokine response during opioid dependence and withdrawal, a period of profound autonomic and emotional upset. Our recent published and preliminary data demonstrate a significant neuroimmune response during withdrawal. These findings suggest that an abrupt cessation of opioid intake leads to an acute central nervous system (CNS) inflammatory response in the central nucleus of the amygdala (CeA), a brain region neuroanatomically associated with affective and cardiorespiratory regulation. It is now reasonable to postulate a chain of proinflammatory responses in a network involving vascular, glial and neuronal cells that comprise this tissue. We propose to now extend the approach developed for this prior work to the specific question of whether similar multi-cell type tissue inflammatory processes underlie opiate withdrawal. We propose a high-dimensional systematic investigation of the CeA inflammatory response in an in vivo rat model of withdrawal aiming to understanding the cell-type specific and molecular framework for neuroinflammatory responses. This will provide potential for improved treatment of opiate withdrawal and its associated pathology. The investigators comprise a collaborative team with the expertise required for this experimental design and analysis, including experts in the molecular effects of opiate exposure and withdrawal in the brain and computational biology and genomics expertise for collection of high dimensional datasets and their analysis and interpretation. We will collect transcriptional and protein data on the molecular and cellular network response in the CeA in order to characterize the cell-type specific contributions of vascular endothelial cells, glia, monocyte lineage cells and neurons to the tissue response. These data will reveal the molecular networks altered within the cell types, their impact on the tissue as a whole, and the resultant neuroinflammatory pathology and neuronal effects that contribute to acute opioid withdrawal's symptomatology.

描述（由申请人提供）：慢性阿片类药物使用改变了大脑状态，包括神经免疫性活动，影响大脑功能和行为，并为持续的药物依赖和病理学做出贡献。但是，几乎没有工作来研究阿片类药物依赖性和戒断过程中细胞因子反应的进展，这是一个深刻的自主和情感沮丧时期。我们最近发表的初步数据表明，在戒断过程中有显着的神经免疫反应。这些发现表明，阿片类药物摄入的突然停止导致急性中枢神经系统（CNS）的炎症反应在杏仁核的中央核（CEA）（CEA）（CEA），这是一种与情感和心脏呼吸器调节相关的脑区域。现在，在涉及构成该组织的血管，神经胶质和神经元细胞的网络中假设一系列促炎反应链是合理的。我们建议现在将针对这项先前工作的方法扩展到一个特定问题，即类似的多细胞组织炎症过程是否是阿片类药物戒断的基础。我们提出了对CEA炎症反应的高维系统研究，旨在理解神经炎症反应的细胞类型特异性和分子框架的戒断模型。这将为改善鸦片戒断及其相关病理的治疗提供潜力。研究人员组成了一个合作团队，具有该实验设计和分析所需的专业知识，包括大脑中鸦片暴露和退出分子效应的专家，以及计算生物学和基因组学专业知识，以收集高维数据集及其分析和解释。我们将收集有关CEA中分子和细胞网络反应的转录和蛋白质数据，以表征血管内皮细胞，神经胶质细胞，单核细胞谱系细胞和神经元对组织反应的细胞类型特异性贡献。这些数据将揭示细胞类型中发生变化的分子网络，它们对整个组织的影响以及由此产生的神经炎性病理学和神经元效应，这会导致急性阿片类药物戒断的症状。