Levodopa dyskinesia and striatal neuroplasticity

左旋多巴运动障碍和纹状体神经可塑性

• 批准号: 7382834
• 负责人: CHRISTINE L KONRADI
• 金额: $ 13.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382834
• 关键词: Parkinson' s disease; abnormal involuntary movement; brain disorder chemotherapy; clinical research; gene expression; human tissue; in situ hybridization; laboratory rat; levodopa; microarray technology; neural plasticity; polymerase chain reaction; postmortem; putamen; striated muscles; western blottings

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a brain disorder caused by progressive loss of the brain chemical dopamine. Patients with Parkinson's disease are treated with levodopa (L-DOPA), a precursor of dopamine. However, L-DOPA therapy has disabling side effects. Most patients on L-DOPA treatment are eventually afflicted with motor fluctuations and abnormal, involuntary movements known as dyskinesias. L-DOPA-induced dyskinesias can become more disabling than Parkinson's disease itself. In severe cases, neurosurgical lesioning of basal ganglia nuclei such as the thalamus, pallidum or subthalamic nucleus is needed to improve Parkinson's disease and to minimize L-DOPA dosage. The proposal is based on the hypothesis that L-DOPA treatment in Parkinson's disease, and L-DOPA-induced dyskinesia, are accompanied by unique patterns of gene expression in the putamen. By comparing the gene expression patterns of dyskinesia to non-dyskinesia, we may find the critical factors responsible for the development of dyskinesia, or responsible for preventing the development of dyskinesia. Specific therapies could then be devised that could be co-administered with L-DOPA to prevent dyskinesias. We propose to investigate the molecular systems that are altered in L-DOPA-induced dyskinesia, and to find the 'molecular signature' of dyskinesia. We will study gene expression patterns in the post mortem putamen in Parkinson's disease in response to L-DOPA treatment (PD; Specific Aim 1) and in response to L-DOPA-induced dyskinesia (Specific Aim 2), and compare it to a rat model of L-DOPA-induced dyskinesia (Specific Aim 3). The role of five candidate genes for the development of, or compensation for, dyskinesia will then be examined in the rat model (Specific Aim 4). In a gene array experiment we have already collected data from the rat model of dyskinesia and assembled lists of candidate genes from these data. The lists of genes will be cross-referenced with the findings in the human putamen to determine five most likely candidates to be tested in the rat model. Hypothesis testing will be combined with computer programs that can find interesting new, unanticipated patterns of gene regulation, and help to formulate new hypotheses. The post mortem samples provide us with direct access to the human condition, while the animal model provides us with an experimental system that can be tightly controlled and that permits functional analyses and hypothesis-testing. Together they can lead the way toward new treatments for dyskinesia.

描述（由申请人提供）：帕金森病（PD）是一种由大脑化学物质多巴胺逐渐丧失引起的脑部疾病。帕金森病患者接受左旋多巴（L-DOPA）（多巴胺的前体）治疗。然而，左旋多巴疗法具有致残的副作用。大多数接受左旋多巴治疗的患者最终都会受到运动波动和异常、不自主运动（称为运动障碍）的困扰。左旋多巴引起的运动障碍可能比帕金森病本身更严重。在严重的情况下，需要对基底神经节核（例如丘脑、苍白球或底丘脑核）进行神经外科损伤，以改善帕金森病并最大限度地减少左旋多巴剂量。该提议基于这样的假设：左旋多巴治疗帕金森病和左旋多巴引起的运动障碍，伴随着壳核中独特的基因表达模式。通过比较运动障碍与非运动障碍的基因表达模式，我们可能会找到导致运动障碍发生或预防运动障碍发生的关键因素。然后可以设计出与左旋多巴联合给药的特定疗法，以预防运动障碍。我们建议研究左旋多巴引起的运动障碍中改变的分子系统，并找到运动障碍的“分子特征”。我们将研究帕金森病死后壳核对 L-DOPA 治疗（PD；具体目标 1）和 L-DOPA 诱导的运动障碍（具体目标 2）的反应的基因表达模式，并将其与大鼠进行比较L-DOPA 诱发的运动障碍模型（具体目标 3）。然后将在大鼠模型中检查五个候选基因在运动障碍发生或补偿中的作用（具体目标 4）。在基因阵列实验中，我们已经从运动障碍大鼠模型中收集了数据，并从这些数据中组装了候选基因列表。基因列表将与人类壳核中的发现进行交叉引用，以确定五个最有可能在大鼠模型中进行测试的候选基因。假设检验将与计算机程序相结合，可以发现有趣的新的、意想不到的基因调控模式，并帮助制定新的假设。尸检样本为我们提供了直接了解人类状况的机会，而动物模型为我们提供了一个可以严格控制并允许进行功能分析和假设检验的实验系统。它们共同可以引领运动障碍新疗法的发展。