Neuropathic mechanisms and gene therapy on opioid dependence

阿片类药物依赖的神经病理机制和基因治疗

基本信息

批准号：
9031097
负责人：
SHUANGLIN HAO
金额：
$ 34.2万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031097
关键词：
Address Agonist Antioxidants Behavior Behavioral Binding Biological Assay CREB1 gene Calcium Cells Chronic Chronic Disease Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein Cytokine Receptors Dependence Development Drug Addiction Drug abuse Elements Gene Targeting HSV vector Health Healthcare Systems Heroin Hyperalgesia Image Image Analysis Immunohistochemistry Mediating Midbrain structure Mitochondria Molecular Molecular Biology Morphine Mus Neuraxis Neuroglia Neurons Neuropathy Opiate Addiction Opiates Opioid Oxidative Stress Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Physical Dependence Process Production Proteins Psychological Dependence Public Health Reactive Oxygen Species Recurrent disease Relapse Role SOD2 gene Second Messenger Systems Signal Transduction Simplexvirus Substance Withdrawal Syndrome Superoxides TLR4 gene TNF gene Testing Transfection Tumor Necrosis Factor Receptor Up-Regulation Withdrawal addiction cell type cytokine density drug abuse prevention gene therapy glial activation insight knock-down midbrain central gray substance neurobiological mechanism neuropathology nonmedical use novel novel therapeutic intervention novel therapeutics opioid abuse opioid withdrawal overexpression pre-clinical receptor response second messenger tempol uptake

项目摘要

DESCRIPTION (provided by applicant): Opioid dependence is a chronic and relapsing disease and characterized by compulsive drug seeking and use. Opioid dependence results in excessive degrees of physical dependence (withdrawal syndrome). Although psychological dependence on opioids is an important feature of dependence/abuse, physical dependence itself (withdrawal syndrome) is a major cause of compulsive drug-taking behavior and short term relapse. Unfortunately, the mechanism of opioid in the pathological changes in opioid dependence is not yet understood in detail. Recent studies show that chronic morphine induces release of proinflammatory cytokines (e.g. TNFα). Oxidative stress may participate in the process of dependence /withdrawal of heroin. However, very few studies have addressed the precise mechanisms by which these glial elements contribute to CNS neuronal TNFR, calcium and ROS response in opioid withdrawal. The role of the PAG in the expression of opioid withdrawal has been suggested by studies, but we know little of the detailed molecular mechanisms. Here, we hypothesize that glial activation resulting in the release of proinflammatory cytokines, and that neurons activated by cytokine receptor induce mitochondrial ROS and pCREB (a key protein in drug abuse behavior) in the development of morphine withdrawal. Specific Aim 1, To test whether glial TLR4 activation induces release of cytokine in morphine withdrawal. Specific Aim 2, To test whether activation of cytokine receptor induces mitochondrial ROS in morphine withdrawal in the PAG. Specific Aim 3, To test whether mitochondrial ROS in the PAG is involved in MW through the pCREB. The proposal will use assays of pharmacology, molecular biology, immunohistochemistry, cell type-targeting gene transfection, and imaging density analysis to complete the novel hypothesis. The results of these studies will provide important insights into the pathogenesis of opioid abuse, and may provide preclinical evidence for a novel therapy of opioid dependence.

描述（由适用提供）：阿片类药物依赖性是一种慢性疾病，其特征是寻求和使用。阿片类药物的依赖性在过度的身体依赖程度（戒断综合征）中导致。尽管对阿片类药物的心理依赖是依赖/滥用的重要特征，但身体依赖本身（戒断综合征）是强迫吸毒行为和短期复发的主要原因。不幸的是，阿片类药物依赖性病理变化中阿片类药物的机制尚未详细理解。最近的研究表明，慢性吗啡诱导促炎细胞因子（例如TNFα）的释放。氧化应激可能参与海洛因的依赖 /戒断过程。但是，很少有研究能够解决这些神经胶质元件在阿片类药物戒断中有助于CNS神经元TNFR，钙和ROS反应的确切机制。研究中，PAG在阿片类药物戒断表达中的作用是通过研究提出的，但我们对详细的分子机制几乎不了解。在这里，我们假设神经胶质激活导致促炎细胞因子释放，而细胞因子受体激活的神经元在形成戒断的发展中诱导了线粒体ROS和PCREB（药物滥用行为的关键蛋白）。特定目标1，以测试Glial TLR4激活诱导释放吗啡戒断中细胞因子的释放。具体目标2，以测试PAG中吗啡戒断中细胞因子受体的激活。特定的目标3，以测试PAG中的线粒体ROS是否通过PCREB参与MW。该提案将使用药理学，分子生物学，免疫组织化学，靶向细胞类型基因转染和成像密度分析的测定法来完成新的假设。这些研究的结果将为阿片类药物的发病机理提供重要的见解，并可能为阿片类药物依赖性的新疗法提供临床前证据。